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  • 1. Alksnis, M.
    et al.
    Lindberg, A Michael
    Department of Medical Genetics, Uppsala University.
    Stålhanske, POK
    Hultberg, H.
    Pettersson, U.
    Use of synthetic oligodeoxyribonucleotides for type-specific identification of coxsackie B viruses1989In: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 3, no 2, p. 103-108Article in journal (Refereed)
    Abstract [en]

    Synthetic oligodeoxyribonucleotides were used for type-specific identification of members of the coxsackie B virus group by nucleic acid hybridization. Two pairs of oligonucleotide chains were constructed based on nucleotide sequences in the VP1 regions of coxsackieviruses B3 and B4. Each labelled probe had a length of 24 nucleotides. The results showed that the oligonucleotide hybridized in a type-specific manner when assayed with extracts from cells infected with all different coxsackie B viruses. A method based on similar principles may thus be used for enterovirus typing.

  • 2.
    Atterby, Clara
    et al.
    Uppsala University.
    Börjesson, Stefan
    National Veterinary Institute.
    Ny, Sofia
    Public Health Agency of Sweden;Karolinska Institutet.
    Järhult, Josef D.
    Uppsala University.
    Byfors, Sara
    Public Health Agency of Sweden.
    Bonnedahl, Jonas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Kalmar County Council;Linköping University.
    ESBL-producing Escherichia coli in Swedish gulls: A case of environmental pollution from humans?2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190380Article in journal (Refereed)
    Abstract [en]

    ESBL-producing bacteria are present in wildlife and the environment might serve as a resistance reservoir. Wild gulls have been described as frequent carriers of ESBL-producing E. coli strains with genotypic characteristics similar to strains found in humans. Therefore, potential dissemination of antibiotic resistance genes and bacteria between the human population and wildlife need to be further investigated. Occurrence and characterization of ESBL-producing E. coli in Swedish wild gulls were assessed and compared to isolates from humans, livestock and surface water collected in the same country and similar time-period. Occurrence of ESBL-producing E. coli in Swedish gulls is about three times higher in gulls compared to Swedish community carriers (17% versus 5%) and the genetic characteristics of the ESBL-producing E. coli population in Swedish wild gulls and Swedish human are similar. ESBL-plasmids IncF-and IncI1-type carrying ESBL-genes blaCTX-M-15 or blaCTX-M-14 were most common in isolates from both gulls and humans, but there was limited evidence of clonal transmission. Isolates from Swedish surface water harbored similar genetic characteristics, which highlights surface waters as potential dissemination routes between wildlife and the human population. Even in a low-prevalence country such as Sweden, the occurrence of ESBL producing E. coli in wild gulls and the human population appears to be connected and the occurrence of ESBL-producing E. coli in Swedish gulls is likely a case of environmental pollution.

  • 3.
    Au, Gough G
    et al.
    The University of Newcastle.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Barry, Richard D
    The University of Newcastle.
    Shafren, Darren R
    The University of Newcastle.
    Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21.2005In: International Journal of Oncology, ISSN 1019-6439, Vol. 26, no 6, p. 1471-6Article in journal (Refereed)
    Abstract [en]

    Cultured melanoma cell lines despite exhibiting similar in vitro morphology, display significant phenotypic and growth rate differences when propagated as in vivo xenografts. Previously we have shown that Coxsackievirus A21 (CVA21) lytically infects in vitro cultures of malignant melanoma cells and is efficient at reducing the tumor burden of mice bearing slow-growing SK-Mel-28 melanoma xenografts. The oncolytic activity of CVA21 against in vivo melanoma xenografts, which possess rapid growth rates and more extensive vascular structure than SK-Mel-28 xenografts warrants further investigation. In the present study we evaluated the oncolytic action of CVA21 against rapidly growing melanoma xenografts (ME4405) which exhibit a highly vascular phenotype. Flow cytometric analysis indicated that in vitro cultures of ME4405 cells expressed comparable levels of the CVA21 cellular receptors, ICAM-1 (intercellular adhesion molecules-1) and DAF (decay accelerating factor) to SK-Mel-28 cells. Despite similar levels of CVA21 receptor expression, SK-Mel-28 cells appear to be more susceptible to viral lysis than ME4405 cells, even though the kinetics of virus replication in both lines was comparable. Intratumoral, intraperitoneal or intravenous administration of CVA21 were equally effective in reducing the tumor volume of ME4405 xenografts in immunodeficient mice, and provides further evidence for the use of CVA21 as a novel oncolytic agent against varying phenotypes of malignant melanoma.

  • 4.
    Bagert, Bodil
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Borrelia burgdorferi: metodutveckling och tillämpning avseende odling och resistensstudier mot komplement, särskilt interaktion med faktor H2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The genus Borrelia is a widespread, pathogenic pest and the causative of among others borreliosis or Lyme disease. The vector for the bacteria is the hard tick, Ixodes ricinus and the infection is transferred through a bite. Untreated, Borrelia may cause arthritis, heart damage or neuroborreliosis. Infection is made possible through different strategies for avoiding the body’s complement system. One such strategy involves the binding of factor H to specific bacterial membrane proteins and, thus, no complement activation and lysis. Another defence mechanism, phagocytosis, acts in cooperation with the complement and is subsequently retarded. The present study includes optimizing of Borrelia culturing, characterisation of different Borrelia strains in regard to sensitivity against the complement including culture counting and the analysis of free C3a and the Terminal Complement Complex (TCC). Further, tagging with FITC in order to study morphology as well as phagocytosis with the aid of microscopy and FACS was performed. The culturing experiments showed Borrelia to be rather easy to culture, although a strict sterile technique has to be applied. Concerning sensitivity to complement, the B.afzelii strains showed to be resistant to complement action, while most of the B. garninii are sensitive. Analysis of C3a and TCC after incubation with normal human blood serum as well as human whole blood, showed that complement activation demands rather or very high cell densities. Tagging with FITC followed by microscopic analysis resulted in good illustrations of the bacterial morphology. The FACS analysis resulted in findings of phagocytosis in both monocytes and granulocytes and, further, the different stages of phagocytosis were visualised through nuclear staining followed by microscopy. The genus Borrelia is a widespread, pathogenic pest and the causative of among others borreliosis or Lyme disease. The vector for the bacteria is the hard tick, Ixodes ricinus and the infection is transferred through a bite. Untreated, Borrelia may cause arthritis, heart damage or neuroborreliosis. Infection is made possible through different strategies for avoiding the body’s complement system. One such strategy involves the binding of factor H to specific bacterial membrane proteins and, thus, no complement activation and lysis. Another defence mechanism, phagocytosis, acts in cooperation with the complement and is subsequently retarded. The present study includes optimizing of Borrelia culturing, characterisation of different Borrelia strains in regard to sensitivity against the complement including culture counting and the analysis of free C3a and the Terminal Complement Complex (TCC). Further, tagging with FITC in order to study morphology as well as phagocytosis with the aid of microscopy and FACS was performed. The culturing experiments showed Borrelia to be rather easy to culture, although a strict sterile technique has to be applied. Concerning sensitivity to complement, the B.afzelii strains showed to be resistant to complement action, while most of the B. garninii

    are sensitive. Analysis of C3a and TCC after incubation with normal human blood serum as well as human whole blood, showed that complement activation demands rather or very high cell densities. Tagging with FITC followed by microscopic analysis resulted in good illustrations of the bacterial morphology. The FACS analysis resulted in findings of phagocytosis in both monocytes and granulocytes and, further, the different stages of phagocytosis were visualised through nuclear staining followed by microscopy.

  • 5.
    Bergdahl, Maria
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Using the counterselectable marker pheS* to study the excision rate and excision patterns of the pathogenicity island of Enterococcus faecalis V583 2009Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The Enterococcus genus consists of natural members of the gastrointestinal tract but they are also opportunistic pathogens. They are a common cause of urinary tract infections but can also cause sepsis and other infections. Enterococcus faecalis and Enterococcus faecium are the most abundant in clinical specimens. Enterococci are a leading cause of nosocomial infections and they have developed resistance against a number of antibiotics e.g. vancomycin. E. faecalis V583 was the first vancomycin resistant isolate reported in the U.S. Movable genetic elements such as pathogenicity islands, PAI, are important for bacterial evolution. PAI:s are large chromosomal fragments mostly seen in pathogenic strains and carry regions such as transposons and insertion elements along with virulence factors and transfer genes. A PAI has been detected in the chromosome of E. faecalis. Excision of PAI:s has been studied for uropathogenic E. coli and frequencies of 10-5 and 10-6 have been reported. In this study the excision rate and excision patterns of E. faecalis V583 was studied using the counterselectable marker pheS*, causing p-Cl-phe sensitivity, and a chloramphenicol resistance gene, cat, inserted at two different positions of the PAI and selecting for excisions by growth on p-Cl-phe. Excision rates of 10-6 and 10-8 were seen based on the p-Cl-phe resistance and chloramphenicol sensitivity. Mutation rate in the pheS* gene was high compared to excision rate which made the method difficult to work with. No obvious excision patterns were detected but the excisions seemed to be limited to the close surroundings of the pheS*/cat insertion.

  • 6.
    Bonnedahl, Jonas
    et al.
    Uppsala University ; Kalmar County Hospital.
    Drobni, P.
    Cent Hosp Växjö.
    Johansson, A.
    Umeå University.
    Hernandez, Jorge
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Melhus, A.
    Uppsala University.
    Stedt, Johan
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Olsen, Björn
    Uppsala University.
    Drobni, M.
    Uppsala University.
    Characterization, and comparison, of human clinical and black-headed gull (Larus ridibundus) extended-spectrum beta-lactamase-producing bacterial isolates from Kalmar, on the southeast coast of Sweden2010In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, no 9, p. 1939-1944Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance is one of the great challenges for modern healthcare. In Gram-negative bacteria, CTX-M-type extended-spectrum beta-lactamases (ESBLs) have been rapidly spreading through Europe since the early 2000s. In Sweden, ESBL-producing Escherichia coli are still rare, but a 3-fold increase has been seen from 2004 to 2007. Enterobacteria and normal flora of wild animals, with or without antibiotic resistance traits, constitute a potential source of human infection and colonization. We studied wild birds with the aim to understand the environmental dissemination of antibiotic resistance and, focusing on clinically relevant resistance types, we made comparisons with human clinical samples. In this study, ESBL-producing human clinical isolates and isolates from juvenile black-headed gulls from Kalmar County hospital and the city of Kalmar, respectively, on the southeast coast of Sweden, were characterized and compared. Despite a low frequency of antibiotic resistance among the isolates from gulls, ESBL-producing E. coli isolates were found, two with bla(CTX-M-14) and one with bla(CTX-M-15). The same CTX-M types were dominant among human ESBL isolates. In addition, gull isolates were dispersed among the human samples in the PhenePlate (TM) clustering system, indicating that they neither differ from the human isolates nor form any separate clonal clustering. The finding of CTX-M-type ESBLs in E. coli isolated from black-headed gulls in Sweden, where 'background resistance' is low, is consistent with an ongoing environmental spread of these plasmid-borne resistance genes. The results indicate that a potential for transfer between the human population and environment exists even in countries with a low level of antibiotic resistance.

  • 7.
    Chryssanthou, E.
    et al.
    Karolinska Univ Hosp.
    Wennberg, H.
    Karolinska Univ Hosp.
    Bonnedahl, Jonas
    Kalmar County Hospital ; Uppsala University.
    Olsen, Björn
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Occurrence of yeasts in faecal samples from Antarctic and South American seabirds2011In: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 54, no 6, p. E811-E815Article in journal (Refereed)
    Abstract [en]

    During an expedition to the Southern Argentinean town of Ushuaia, the Antarctic Peninsula, Antarctic Islands and the Falkland Islands, we collected 94 faecal specimens from wild birds to screen for yeast within the different bird species. The yeast species were identified by morphological features and commercial characterisation kits. From 54% of the specimens, we isolated 122 strains representing 29 yeast species. Debaryomyces hansenii, Candida lambica and Candida krusei were the most frequently isolated species. We found a plethora of yeasts in birds living in proximity to humans, whereas birds living in more remote areas were colonised with a lower number of fungal species.

  • 8.
    Demirel, Isak
    et al.
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Säve, Susanne
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kruse, Robert
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Persson, Katarina
    Univ Örebro, Dept Clin Med, Sch Hlth & Med Sci, Örebro, Sweden.
    Expression of suppressor of cytokine signalling 3 (SOCS3) in human bladder epithelial cells infected with uropathogenic Escherichia coli2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 2, p. 158-167Article in journal (Refereed)
    Abstract [en]

    Suppressor of cytokine signalling (SOCS) proteins inhibit pro-inflammatory signalling mediated by Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathways. To evade the immune response some pathogens appear to modify the host SOCS proteins. Uropathogenic Escherichia coli (UPEC) are able to subvert the host response evoked by bladder epithelial cells, but the mechanisms are not fully understood. The objective of this study was to investigate whether UPEC can modify the host SOCS and STAT3 response. Real time RT-PCR studies demonstrated an increased SOCS1 and SOCS3 expression in the isolated human bladder epithelial cell lines (RT-4 and 5637) in response to cytokines. UPEC strain IA2 increased SOCS3, but not SOCS1, mRNA levels with a peak at 6h after infection. The increase of SOCS3 was confirmed at the protein level by Western blotting. The UPEC strain IA2 caused a time-dependent decrease in the phosphorylation of STAT3. This study demonstrates that UPEC are able to affect SOCS3 and STAT3 signalling in human uroepithelial cells. The finding that UPEC are able to induce mediators involved in suppression of host cytokine signalling may help to elucidate how UPEC may circumvent the host response during urinary tract infection.

  • 9.
    Ekström, Jens-Ola
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ljungan Virus Replication in Cell Culture2007Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Ljungan virus (LV) is a recently identified picornavirus of the genus Parechovirus. LV has been isolated from voles trapped in Sweden and also in the United States. LV infected small rodents may suffer from diabetes type 1 and type 2 like symptoms, myocarditis and encephalitis. LV has been proposed as a human pathogen, with indications of causing diabetes type 1, myocarditis and intrauterine fetal deaths.

    In this thesis, cell culture adapted LV strains were utilised for development and adaptation of several basic methodological protocols to study the LV biology, e.g. real time PCR, highly specific antibodies and a reverse genetics system. These methods allowed detailed studies of this virus and how it interacts with the host cell. The genomic 5'-end was identified and modelling showed unique secondary structure folding of this region. The LV encodes an aphthovirus-like 2A protein with a DvExNPGP motif. This motif was found to mediate primary cleavage of the LV polyprotein in vitro and is proposed to constitute the carboxy terminus of the structural protein VP1 in LV. Rabbit polyclonal antibodies generated against recombinant structural proteins were used to verify that the LV virion is composed of the structural proteins VP0, VP1 and VP3. Cell culture studies showed that LV replicates to low titer with an absent or delayed cell lysis. LV is proposed to be able to spread by a, for picornaviruses, not previously demonstrated direct cell-to-cell transmission. All results taken together suggest a maintenance strategy of LV including low amounts of the LV genome and persistently infected hosts. Stability studies showed that the LV virion not only maintain activity in acidic and alkaline environments but also exhibit resistance to the commonly used disinfectant Virkon®.The results presented in this thesis show that LV has several unique properties, not previously observed for a picornavirus.

  • 10.
    Ekström, Jens-Ola
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Tolf, Conny
    Edman, Kjell
    Lindberg, Michael
    A novel mechanism for maturation of the VP1 protein of Ljungan virusManuscript (preprint) (Other (popular science, discussion, etc.))
  • 11.
    Elfving, Karin
    et al.
    Uppsala University Hospital ; Falu Hospital.
    Olsen, Björn
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University Hospital.
    Bergström, Sven
    Umeå University.
    Waldenström, Jonas
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University Hospital.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control.
    Sjöstedt, Anders
    Umeå University Hospital.
    Mejlon, Hans
    Uppsala University.
    Nilsson, Kenneth
    Uppsala University Hospital ; Falu Hospital ; Uppsala University.
    Dissemination of Spotted Fever Rickettsia Agents in Europe by Migrating Birds2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, article id e8572Article in journal (Refereed)
    Abstract [en]

    Migratory birds are known to play a role as long-distance vectors for many microorganisms. To investigate whether this is true of rickettsial agents as well, we characterized tick infestation and gathered ticks from 13,260 migratory passerine birds in Sweden. A total of 1127 Ixodes spp. ticks were removed from these birds and the extracted DNA from 957 of them was available for analyses. The DNA was assayed for detection of Rickettsia spp. using real-time PCR, followed by DNA sequencing for species identification. Rickettsia spp. organisms were detected in 108 (11.3%) of the ticks. Rickettsia helvetica, a spotted fever rickettsia associated with human infections, was predominant among the PCR-positive samples. In 9 (0.8%) of the ticks, the partial sequences of 17kDa and ompB genes showed the greatest similarity to Rickettsia monacensis, an etiologic agent of Mediterranean spotted fever-like illness, previously described in southern Europe as well as to the Rickettsia sp. IrITA3 strain. For 15 (1.4%) of the ticks, the 17kDa, ompB, gltA and ompA genes showed the greatest similarity to Rickettsia sp. strain Davousti, Rickettsia japonica and Rickettsia heilongjiangensis, all closely phylogenetically related, the former previously found in Amblyomma tholloni ticks in Africa and previously not detected in Ixodes spp. ticks. The infestation prevalence of ticks infected with rickettsial organisms was four times higher among ground foraging birds than among other bird species, but the two groups were equally competent in transmitting Rickettsia species. The birds did not seem to serve as reservoir hosts for Rickettsia spp., but in one case it seems likely that the bird was rickettsiemic and that the ticks had acquired the bacteria from the blood of the bird. In conclusion, migratory passerine birds host epidemiologically important vector ticks and Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents and their diseases.

  • 12.
    Elvingson, Ebba
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Art- och genusbestämning av bakterier direkt från blododlingar med MALDI-TOF MS2014Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Sepsis är ett allvarligt tillstånd som uppstår när bakterier går från vävnad till blodbanan. Positiva blododlingar odlas på agarplattor och bakterier analyseras med Matrix Assisted Laser Desorption Ionisation Time-of-flight Mass spectrometry (MALDI-TOF MS) där prov blandas med en matrix och sedan bestrålas med laser. Proteinerna i provet joniseras och rör sig mot en detektor, vilket ger ett m/z-spektrum som jämförs med referensspektrum i en databas och ett score-värde erhålls över hur väl analyten liknar referensen. Arbetets syfte var att undersöka möjligheten att direktidentifiera bakterier från blod med en viss preparation innan analys med MALDI-TOF MS och på så vis möjliggöra snabbare preliminära svar samt undersöka möjligheten att särskilja Staphylocoocus aureus och koagulasnegativa stafylokocker. Innan analys med MALDI-TOF MS centrifugerades blod från positiva blododlingar blod i flera steg med 5 % natriumkloridlösning (NaCl-metoden). Dessutom testades ett kommersiellt kit (Sepsityper, Bruker Daltonics). Med NaCl-metoden sågs korrekt identifiering hos 66 % av inokulerade proverna. Av blododlingar innehållande med S. aureus respektive koagulasnegativa stafylokocker identifierades 60 % respektive 43 % av bakterierna korrekt. Med Sepsiptyper erhöll 58 % av proverna godkänt score-värde. Slutsatsen blev att det är möjligt att identifiera bakterier direkt från blod efter viss preparation, men metoden bör utvecklas mer då det fanns en signifikant skillnad i score mellan NaCl-metoden och nuvarande metod. Det är dock möjligt att skilja mellan Staphylococcus aureus och koagulasnegativa stafylokocker. Fler studier är nödvändiga för att avgöra möjligheten att föra in någon av metoderna i rutindiagnostiken.

  • 13.
    Forsman, L. Davies
    et al.
    Karolinska Inst ; Karolinska Univ Hosp Solna.
    Schön, Thomas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Linköping University.
    Simonsson, U. S. H.
    Uppsala University.
    Bruchfeld, J.
    Karolinska Inst ; Karolinska Univ Hosp Solna.
    Larsson, M.
    Linköping University.
    Jureen, P.
    Publ Hlth Agcy Sweden.
    Sturegard, E.
    Regional and University Laboratories, Region Skåne.
    Giske, C. G.
    Karolinska Univ Hosp.
    Angeby, K.
    Karolinska Univ Hosp;Univ W Indies.
    Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 12, p. 7557-7559Article in journal (Refereed)
    Abstract [en]

    We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC(0-24)/MIC) using >= 25 as a potential target, the cumulative fraction response was >= 90% at doses of >= 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

  • 14.
    Frejd, Rebecka
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Vad är känt om Zikavirusets spridning, dess kliniska bild, patogenes, morfologi, diagnostik samt behandling?2017Independent thesis Basic level (university diploma), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Zikaviruset är ett virus som fått stor uppmärksamhet i framför allt Sydamerika från 2015 och framåt då allt fler fall uppmärksammats. Detta arbete har utförts som en litteraturstudie med mål att sammanfatta kunskapsläget kring Zikavirusets morfologi, spridning, historia, komplikationer, diagnostik samt rådande behandlingsmöjligheter. Som källor används information från Folkhälsomyndigheten, CDC, PAHO och WHO samt MeSH-sökningar via PubMed.

    Viruset tillhör familjen Flaviviridae. Liknande andra virus i samma grupp kan infektionen ge feber, makulopapulösa hudutslag, konjunktivit, ledvärk, huvudvärk och myalgi. Det beskrevs först redan på slutet av 1940-talet i Afrika och har sedan rapporterats ha spridit sig till Asien, Oceanien, Stilla havsöarna och nu senast med utbrott i Sydamerika. Virusinfektionen har blivit mycket omdiskuterad då allt mer bevis kunnat läggas fram för att den kan leda till Guillain-Barrés syndrom samt även utöva teratogena effekter med mikrocefali som följd. Man har kartlagt spridning framför allt via myggarten Aedes men bevis finns även för att sexuell spridning kan ske samt att sjukdomen förefaller även kunna spridas från mor till foster. Diagnostiken baseras på RT-PCR och serologiska tester. I nuläget finns ingen aktiv behandling. Sammanfattningsvis har Zikavirus spridit sig snabbt genom Syd- och latinamerika sista åren och visat sig utgöra ett hot mot folkhälsan i dessa områden varför ett framtagande av ett fungerande vaccin är önskvärt.

  • 15.
    Fridlund, Jimmy
    et al.
    Kalmar County Hospital.
    Woksepp, Hanna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Kalmar County Hospital.
    Schön, Thomas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Kalmar County Hospital ; Linköping University.
    A microbiological method for determining serum levels of broad spectrum β-lactam antibiotics in critically ill patients2016In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 129, p. 23-27Article in journal (Refereed)
    Abstract [en]

    Background Recent studies show that suboptimal blood levels of β-lactam antibiotics are present in intensive care unit (ICU) patients. A common reference method for assessing drug concentrations is liquid chromatography coupled with mass-spectrometry (LC-MS) which is highly accurate but rarely available outside reference centres. Thus, our aim was to develop a microbiological method for monitoring β-lactam antibiotic serum levels which could be used at any hospital with a microbiological laboratory. Methods The method was developed as a 96-well broth microdilution format to assess the concentrations of cefotaxime (CTX), meropenem (MER), and piperacillin (PIP). Patient serum containing antibiotics were diluted in suspensions of bacteria with known minimal inhibitory concentrations (MICs). Serum antibiotic concentrations were calculated by dividing the MIC with the dilution factor at which the serum inhibited growth of the bacterial suspension. Serum (n = 88) from ICU patients at four hospitals in south-east Sweden were analysed and compared to LC-MS analysis. Results The overall accuracy and precision for spiked samples and patient samples was within the pre-set target of ± 20.0% for all drugs. There was a significant correlation between the microbiological assay and LC-MS for the patient samples (CTX: r = 0.86, n = 31; MER: r = 0.96, n = 11; PIP: r = 0.88, n = 39) and the agreement around the clinical cut-off for CTX (4.0 mg/l), MER (2.0 mg/l) and PIP (16.0 mg/l) was 90%, 100% and 87%, respectively. Conclusion The microbiological method has a performance for determination of serum levels of meropenem, piperacillin and cefotaxime suitable for clinical use. It is an inexpensive method applicable in any microbiology laboratory.

  • 16.
    Gregeby, Erik
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Engineering.
    Welander, Ulrika
    Linnaeus University, Faculty of Science and Engineering, School of Engineering.
    The influence of mixing, addition of buffer, silage and chicken manure on the biogas production from cattle manure2010In: 18th European Biomass Conference and Exhibition, 3-7 May, Lyon, ETA Renewable Energies and WIP Renewable Energies , 2010Conference paper (Refereed)
    Abstract [en]

    A number of batch experiements were performed in order to evaluate the biogas production from cattle manure adter addition of buffer, silage or chicken manure. Some experiments were also performed to investigate the effect of mixing. All experiments were performed at 35 C. The results showed that the extent of mixing did not affect the biogas production to any larger extent. The addition of buffer speeds up the start of the process and increased the volume of biogas produced. The methane content was approximately the same independently on if a buffer was added or not. Chicken manure inhibited the process adn addition of silage gave an increase in the amount of biogas produced. No significant effect of silage addition was found on the methane content of the biogas.

  • 17.
    Gullberg, Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Tolf, Conny
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Mulders, Mick N
    Savolainen-Kopra, Carita
    Hovi, Tapani
    Van Ranst, Marc
    Lemey, Philippe
    Hafenstein, Susan
    Lindberg, A. Michael
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Characterization of a putative ancestor of coxsackievirus B5.2010In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 84, p. 9695-9708Article in journal (Refereed)
    Abstract [en]

    Like other RNA viruses, coxsackievirus B5 (CVB5) exists as circulating heterogeneous populations of genetic variants. In this study, we present the reconstruction and characterization of a probable ancestral virion of CVB5. Phylogenetic analyses based on capsid protein encoding regions (the VP1 gene of 41 clinical isolates and the entire P1 region of eight clinical isolates) of CVB5 revealed two major co-circulating lineages. Ancestral capsid sequences were inferred from sequences of these contemporary CVB5 isolates using maximum likelihood methods. By using Bayesian phylodynamic analysis, the inferred VP1 ancestral sequence was dated back to 1854 (1807-1898). In order to study the properties of the putative ancestral capsid, the entire ancestral P1 sequence was synthesized de novo and inserted into the replicative backbone of an infectious CVB5 cDNA clone. Characterization of the recombinant virus in cell culture showed that fully functional infectious virus particles were assembled and that these viruses displayed properties similar to those of modern isolates, in terms of receptor preferences, plaque phenotype, growth characteristics and cell tropism. This is the first report describing resurrection and characterization of a picornavirus with a putative ancestral capsid. Our approach, including phylogenetics-based reconstruction of viral predecessors, could serve as a starting point for experimental studies of viral evolution and might also provide an alternative strategy in the development of vaccines.

  • 18.
    Gullberg, Maria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Tolf, Conny
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Polacek, Charlotta
    Precechtelova, Jana
    Badurova, Miriam
    Sojka, Martin
    Mohlin, Camilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Israelsson, Stina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Johansson, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bopegamage, Shubhada
    Hafenstein, Susan
    Lindberg, A. Michael
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    A single coxsackievirus B2 capsid residue controls cytolysis and apoptosis in rhabdomyosarcoma cells.2010In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 84, no 12, p. 5868-5879Article in journal (Refereed)
    Abstract [en]

    Coxsackievirus B2 (CVB2), one of six human pathogens of the group B coxsackieviruses within the enterovirus genus of Picornaviridae, causes a wide spectrum of human diseases ranging from mild upper respiratory illnesses to myocarditis and meningitis. The CVB2 prototype strain Ohio-1 (CVB2O) was originally isolated from a patient with summer grippe in the 1950s. Later on, CVB2O was adapted to cytolytic replication in rhabdomyosarcoma (RD) cells. Here, we present analyses of the correlation between the adaptive mutations of this RD variant and the cytolytic infection in RD cells. Using reverse genetics, we identified a single amino acid change within the exposed region of the VP1 protein (glutamine to lysine at position 164) as the determinant for the acquired cytolytic trait. Moreover, this cytolytic virus induced apoptosis, including caspase activation and DNA degradation, in RD cells. These findings contribute to our understanding of the host cell adaptation process of CVB2O and provide a valuable tool for further studies of virus-host interactions.

  • 19.
    Huang, Yanyan
    et al.
    Memorial University of Newfoundland, Canada.
    Wille, Michelle
    Memorial University of Newfoundland, Canada.
    Benkaroun, Jessica
    Memorial University of Newfoundland, Canada.
    Munro, Hannah
    Memorial University of Newfoundland, Canada.
    Bond, Alexander L.
    Memorial University of Newfoundland, Canada.
    Fifield, David A.
    Newfoundland and Labrador Department of Natural Resources, Canada.
    Robertson, Gregory J.
    Environment Canada, Canada.
    Ojkic, Davor
    University of Guelph, Canada.
    Whitney, Hugh
    Newfoundland and Labrador Department of Natural Resources, Canada.
    Lang, Andrew S.
    Memorial University of Newfoundland, Canada.
    Perpetuation and reassortment of gull influenza A viruses in Atlantic North America2014In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 456-457, p. 353-363Article in journal (Refereed)
    Abstract [en]

    Gulls are important hosts of avian influenza A viruses (AIVs) and gull AIVs often contain gene segments of mixed geographic and host lineage origins. In this study, the prevalence of AIV in gulls of Newfoundland, Canada from 2008 to 2011 was analyzed. Overall prevalence was low (30/1645, 1.8%) but there was a distinct peak of infection in the fall. AIV seroprevalence was high in Newfoundland gulls, with 50% of sampled gulls showing evidence of previous infection. Sequences of 16 gull AIVs were determined and analyzed to shed light on the transmission, reassortment and persistence dynamics of gull AIVs in Atlantic North America. Intercontinental and waterfowl lineage reassortment was prevalent. Of particular note were a wholly Eurasian AIV and another with an intercontinental reassortant waterfowl lineage virus. These patterns of geographic and inter-host group transmission highlight the importance of characterization of gull AIVs as part of attempts to understand global AIV dynamics.

  • 20.
    Idh, Jonna
    et al.
    Linköping University.
    Andersson, Blanka
    Linköping University.
    Lerm, Maria
    Linköping University ; Karolinska Institutet.
    Raffetseder, Johanna
    Linköping University.
    Eklund, Daniel
    Linköping University.
    Woksepp, Hanna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Kalmar County Hospital.
    Werngren, Jim
    Public Health Agency Sweden.
    Mansjo, Mikael
    Public Health Agency Sweden.
    Sundqvist, Tommy
    Linköping University.
    Stendahl, Olle
    Linköping University.
    Schön, Thomas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Linköping University ; Kalmar County Hospital.
    Reduced susceptibility of clinical strains of Mycobacterium tuberculosis to reactive nitrogen species promotes survival in activated macrophages2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0181221Article in journal (Refereed)
    Abstract [en]

    Background Drugs such as isoniazid (INH) and pretomanid (PRT), used against Mycobacterium tuberculosis are active partly through generation of reactive nitrogen species (RNS). The aim of this study was to explore variability in intracellular susceptibility to nitric oxide (NO) in clinical strains of M. tuberculosis. Method Luciferase-expressing clinical M. tuberculosis strains with or without INH resistance were exposed to RNS donors (DETA/NO and SIN-1) in broth cultures and bacterial survival was analysed by luminometry. NO-dependent intracellular killing in a selection of strains was assessed in interferon gamma/lipopolysaccharide-activated murine macrophages using the NO inhibitor L-NMMA. Results When M. tuberculosis H37Rv was compared to six clinical isolates and CDC1551, three isolates with inhA mediated INH resistance showed significantly reduced NO-susceptibility in broth culture. All strains showed a variable but dose-dependent susceptibility to RNS donors. Two clinical isolates with increased susceptibility to NO exposure in broth compared to H37Rv were significantly inhibited by activated macrophages whereas there was no effect on growth inhibition when activated macrophages were infected by clinical strains with higher survival to NO exposure in broth. Furthermore, the most NO-tolerant clinical isolate showed increased resistance to PRT both in broth culture and the macrophage model compared to H37Rv in the absence of mutational resistance in genes associated to reduced susceptibility against PRT or NO. Conclusion In a limited number of clinical M. tuberculosis isolates we found a significant difference in susceptibility to NO between clinical isolates, both in broth cultures and in macrophages. Our results indicate that mycobacterial susceptibility to cellular host defence mechanisms such as NO need to be taken into consideration when designing new therapeutic strategies.

  • 21.
    Israelsson, Stina
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Gullberg, Maria
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Roivainen, Merja
    Edman, Kjell
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Studies of Echovirus 5 interactions with the cell surface: Heparan sulfate mediates attachment to the host cell.2010In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 151, no 2, p. 170-176Article in journal (Refereed)
    Abstract [en]

    Infections caused by Echovirus 5 (E5), an enterovirus of the Picornaviridae family, have been associated with fever, rashes and sporadic cases of aseptic meningitis. To elucidate the receptor usage of this virus, the significance of a previously proposed integrin binding arginine-glycine-aspartic acid (RGD) motif found in the VP3 capsid protein was investigated, as well as the capacity of E5 to interact with heparan sulfate on the cell surface. Using the prototype strain E5 Noyce (E5N), an E5N mutant where the aspartic acid of the RGD motif has been substituted to a glutamic acid and clinical E5 isolates, the RGD motif of VP3 was found to be non-essential and hence not involved in integrin receptor binding. However, E5N and clinical E5 isolates interact with heparan sulfate at the cell surface, as demonstrated by virus replication inhibition assays using heparin and heparinase III, and studies of E5 interactions at the cell surface measured by real-time PCR analysis. In conclusion, E5 utilizes heparan sulfate as a cellular receptor, but the RGD motif of VP3 is not essential for E5 infectivity.

  • 22. Jaenson, Thomas G. T.
    et al.
    Bergström, Sven
    Mejlon, H. A.
    Noppa, Laila
    Olsen, Björn
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Tälleklint, L
    The ecology of lyme borreliosis in Sweden1994In: Lyme borreliosis: proceedings of a NATO ARW held in London, United Kingdom, May 19-20, 1993 / [ed] John S. Axford and David H. E. Rees, New York: Springer-Verlag New York, 1994, 1, p. 113-115Conference paper (Other academic)
    Abstract [en]

    The geographical distribution of Lyme borreliosis (Lb) in the North European countries appears to coincide with the geographical distribution of the principal vector, the common tick Ixodes ricinus. We have found that in Sweden this tick species occurs in the southern and south-central parts of the country and along the coast of northern Sweden. This area corresponds with the distributional area of Lyme borreliosis. I. ricinus, and thus also Borrelia burgdorferi s.l., are in general not present in the interior of North Sweden, presumably because the climate is too harsh for the vector.

  • 23.
    Jansson, Alexandra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Effekten och potentiella risker med bedaquiline, delamanid och pretomanid vid behandling av multiresistent tuberkulos2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Archeological findings of tuberculosis can be found way back to the Stone Age but it wasn’t before the 18th century that Robert Koch discovered that it was Mycobacterium tuberculosis (M. tuberculosis) who caused the disease tuberculosis. Current data indicates that approximately 10 million people are infected with tuberculosis each year and 600 000 new cases of multidrug resistance tuberculosis (MDR-TB) was observed in 2017.  Tuberculosis is a bacterium with a unique cell wall consisting of a high concentration of mycolic acid. The fatty cell wall of the bacteria can act as a barrier against antituberculotic drugs, making the disease difficult to treat. Tuberculosis is a disease who can be spread among people via airborne droplets but only about 10 % of all people who are infected are affected by disease symptoms.  Tuberculosis is usually diagnosed by spot-sputum samples from deep within the airways. Resistance to antituberculotic drugs are detected by culture growth of the bacteria on either a liquid or solid medium. Tuberculosis is treated with a combination of several different drugs such as isoniazide, rifampicine, pyrazinamide and ethambutol. Also called HRZE and is a standard regimen for tuberculosis. If treatment occurs incorrectly or is incomplete the bacteria can develop resistance to these drugs and MDR-TB can emerge. Patients with MDR-TB is usually resistant to either or both isoniazide and rifampicine which makes the disease difficult to treat and another combination of drugs is needed. Bedaquiline, delamanide and pretomanide are newly developed drugs that can hopefully be used in the treatment of MDR-TB.

    The purpose of the thesis was to analyze the efficacy and potential risks with bedaquiline, delamanide and pretomanide in the treatment of MDR-TB. The articles for this literature study were obtained from the two databases PubMed and ClinicalTrials. A total of 7 articles were chosen to analyze the efficacy and potential risks with bedaquiline, delamanide and pretomanid used in treatment in patients with MDR-TB.

    The result obtained from the articles was obtained by primarily analyzing the primary outcome from each article. All articles suggest that bedaquiline, delamanide and pretomanide have a favorable bactericidal efficacy against M. tuberculosis and may shorten the treatment period. However, all of the studied drugs produced numerous side effects such as headaches, nausea, dizziness, hyperuricemia and an extended QT interval. Although all the side effects that occurred in the studies were classified as mild to moderate. Many side effects occurred in the studies and only a few participants participated in each study. However, it was observed that the new combinations with bedaquiline, delamanide and pretomanide can reduce the development of additional drug resistance. Despite some deviations in the studies, bedaquiline, delamanide and pretomanid may be new alternative treatments for MDR-TB. But more studies with a larger study population is needed to ensure the safety profile and efficacy of all of the drugs above. However, bedaquiline, delamanide and pretomanid show promising results in current studies for the future fight against MDR-TB.

  • 24.
    Jansson, Johan
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. University of Rochester, USA.
    Hsu, Yu-Chiao
    University of Rochester, USA.
    Kuzin, Igor I.
    University of Rochester, USA.
    Campbell, Andrew
    University of Rochester, USA.
    Mullen, Craig A.
    University of Rochester, USA.
    Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 6, p. 800-807Article in journal (Refereed)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analysed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.

  • 25.
    Johannesson, Per
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Israelsson, Stina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Edman, Kjell
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    A novel and rapid method to quantify cytolytic replication of picornaviruses in cell culture2005In: Journal of virological methods, Vol. 130, p. 117-123Article in journal (Refereed)
    Abstract [en]

    Determining viral titers is a key issue in a wide variety of studies regarding different aspects of virology. The standard methods used for determining picornavirus titers are endpoint titration assay and plaque assay, both time consuming and laborious. The method described uses the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide) that is reduced to formazane by cellular dehydrogenase, genes shown to be down-regulated during picornavirus infection. The amount formazane produced correlates with the viral titers obtained and can easily be measured using an ELISA plate reader. The colorimetric method has been evaluated using virus types from different genera of the Picornaviridae family. The MTT method reduces the time spent on determining the viral titers and still maintains a reliable accuracy.

  • 26.
    Johansson, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Genomic Organization and Capsid Architecture of Ljungan Virus: a Novel Member of the Picornaviridae2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [sv]

    Ljungan virus är ett virus som isolerades i Sverige i mitten på nittiotalet. Under perioden 1989-1992 avled flera svenska elitorienterare plötsligt i hjärtmuskelinflammation. Man misstänkte att orienterarna kunde ha utsatts för en vektorburen infektion eftersom de exponeras för djur som finns i skog och mark under träning och tävling. Det är sedan tidigare känt att sorkar är den naturliga reservoaren för ett annat virus (Puumala virus) som kan orsaka njurskada hos människor. Sorkantalet i vissa delar av Sverige varierar kraftigt från år till år i ett cykliskt förlopp. Man fann ett samband mellan antalet sorkar och förekomsten av hjärtmuskelinflammation, typ 1 diabetes och Guillain-Barre's syndrom vilket ledde till att ett tidigare okänt virus, Ljungan virus, kunde isoleras från sorkar. Detta virus är ett litet RNA-virus som tillhör familjen Picornavirus. Till denna familj hör också flera kända virus såsom många av våra vanligt förekommande förkylningsvirus, men också virus som kan orsaka svåra sjukdomar, till exemel poliovirus och mul- och klövsjukevirus.

    Ljungan virus är ett nyupptäckt virus och därför är kunskapen om viruset begränsad. För att öka vår förståelse om viruset så har arvsmassan för tre svenska isolat (87-012, 174F och 145SL) av Ljungan virus kartlagts (artikel IV). Denna studie visade att Ljungan virusets arvmassa har flera unika egenskaper. Släktskapstudier visade att Ljungan virus är endast avlägset släkt med redan kända picornavirus och viruset bör därför utgöra en egen undergrupp i familjen (artikel III). Med kunskap om Ljungan virusets arvsmassa så var det möjligt att visa att Ljungan virus förekommer även på andra ställen än i Sverige (artikel VI). I mitten på 60-talet isolerades ett virus, M1146, från sork som fångats i Oregon, USA. Baserat på egenskaper hos proteinhöljet (kapsiden) så antog man då att M1146 var ett picornavirus. Studier av arvsmassan för detta virus visade att M1146 är närmast besläktat med de svenska Ljungan virus isolaten och har samma unika egenskaper i sin arvsmassa (artikel VI). Dessa studier har varit möjliga eftersom vi tidigare har utvecklat en metod för att producera stora mängder av hela arvsmassan (artikel I och II).

    Slutligen har det proteinhölje som innesluter och skyddar Ljungan virusets arvsmassa studerats (artikel V). Dessa studier visade att kapsiden är uppbyggd av tre proteiner och inte fyra som hos de flesta picornavirus. Dessa studier underlättades av att en enkel och effektiv metod för att odla Ljungan virus i provröret har utvecklats (artikel V). Sammantaget så har dessa studier försett oss med nya kunskaper om Ljungan virus som möjliggör fortsatta studier av dess biologi och eventuella förmåga att orsaka sjukdom hos människor och djur.

  • 27.
    Johansson, Susanne
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ekström, Jens-Ola
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Shafren, Darren
    Frisk, Gun
    Hyypiä, Timo
    Edman, Kjell
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lindberg, Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Cell culture propagation and biochemical analysis of the Ljungan virus prototype strain2004In: Biochemical and Biophysical Research Communication, Vol. 317, no 4, p. 1023-1029Article in journal (Refereed)
    Abstract [en]

    Ljungan virus (LV) is proposed as a potentially important rodent harbored viral human pathogen. Little is known about the biophysical nature of the virus and despite being molecularly characterized, progress in epidemiological and basic biological studies of LV has been hampered by the lack of a robust and reliable cell culture propagation system. Here we report the first description of an efficient lytic multi-cycle cell culture propagation of the LV prototype strain (87-012). Biophysical analysis of gradient purified LV virions generated by this system identified mature infectious virions to possess a sedimentation coefficient of 160S and in agreement with previous molecular prediction, polyprotein analysis suggests that the native virion is composed of only three major structural proteins. The nucleotide composition of the complete genome of the LV cell culture adapted virus was determined and compared to that of the parental prototype LV. Numerous mutations were observed scattered throughout the viral genome and particularly in VP1. The development of this cell culture system for LV should open new avenues in the study of LV biology, structure, pathogenesis, and prevalence of natural infection in the wider community.

  • 28.
    Johansson, Susanne
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Niklasson, Bo
    Maizel, Jacob
    Gorbalenya, Alexander
    Lindberg, Michael
    Molecular analysis of three Ljungan virus isolates reveals a new, close-to-root lineage of the Picornaviridae with a cluster of two unrelated 2A proteins2002In: Journal of Virology, ISSN 0022-538X (print) 1098-5514 (online), Vol. 76, no 17, p. 8920-8930Article in journal (Refereed)
  • 29.
    Jourdain, Elsa
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. INRA, France.
    Gunnarsson, Gunnar
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Kristianstad University.
    Wahlgren, John
    Karolinska Institutet ; Swedish Institute for Infectious Disease Control.
    Latorre-Margalef, Neus
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Bröjer, Caroline
    National Veterinary Institute ; University of Agricultural Sciences.
    Sahlin, Sofie
    Karolinska Institutet ; Swedish Institute for Infectious Disease Control.
    Svensson, Lovisa
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Waldenström, Jonas
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control.
    Olsen, Björn
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Influenza Virus in a Natural Host, the Mallard: Experimental Infection Data2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, article id e8935Article in journal (Refereed)
    Abstract [en]

    Wild waterfowl, particularly dabbling ducks such as mallards (Anas platyrhynchos), are considered the main reservoir of low-pathogenic avian influenza viruses (LPAIVs). They carry viruses that may evolve and become highly pathogenic for poultry or zoonotic. Understanding the ecology of LPAIVs in these natural hosts is therefore essential. We assessed the clinical response, viral shedding and antibody production of juvenile mallards after intra-esophageal inoculation of two LPAIV subtypes previously isolated from wild congeners. Six ducks, equipped with data loggers that continually monitored body temperature, heart rate and activity, were successively inoculated with an H7N7 LPAI isolate (day 0), the same H7N7 isolate again (day 21) and an H5N2 LPAI isolate (day 35). After the first H7N7 inoculation, the ducks remained alert with no modification of heart rate or activity. However, body temperature transiently increased in four individuals, suggesting that LPAIV strains may have minor clinical effects on their natural hosts. The excretion patterns observed after both reinoculations differed strongly from those observed after the primary H7N7 inoculation, suggesting that not only homosubtypic but also heterosubtypic immunity exist. Our study suggests that LPAI infection has minor clinically measurable effects on mallards and that mallard ducks are able to mount immunological responses protective against heterologous infections. Because the transmission dynamics of LPAIVs in wild populations is greatly influenced by individual susceptibility and herd immunity, these findings are of high importance. Our study also shows the relevance of using telemetry to monitor disease in animals.

  • 30.
    Järhult, Josef
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Muradrasoli, Shaman
    Wahlgren, John
    Söderström, Hanna
    Orozovic, Goran
    Gunnarsson, Gunnar
    Bröjer, Caroline
    Latorre-Margalef, Neus
    Fick, Jerker
    Grabic, Roman
    Lennerstrand, Johan
    Waldenström, Jonas
    Lundkvist, Åke
    Olsen, Björn
    Environmental levels of oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards – implications for the risk of an oseltamivir resistant influenza pandemicManuscript (preprint) (Other academic)
    Abstract [en]

    Resistance in influenza is a growing problem. Oseltamivir carboxylate (OC), the active substance of the most widely used antiviral drug oseltamivir (Tamiflu ®), is poorly degraded in sewage treatment plants and surface water. OC has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to it. To test if resistance can occur in this situation, we infected mallards with influenza A/H1N1 virus and exposed the birds to 0.08 μg /L, 1.00 μg/L and 80.00 μg/L of OC. The resistance mutation H274Y occurred at 1 μg/L and rapidly dominated the viral population at 80 μg/L. The environmental levels of OC are expected to reach this magnitude. IC50 for OC was increased from 1-4 nM to 400-700 nM in H274Y-positive isolates, confirming a resistant phenotype. As influenza viruses can cross the species barrier, resistance to oseltamivir can spread to human-adapted strains with pandemic potential disabling one of the cornerstones in pandemic preparedness planning.

  • 31.
    Kakooza-Mwesige, Angelina
    et al.
    Makerere Univ, Uganda;Mulago Hosp, Uganda.
    Mohammed, Abdul K. H.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Psychology.
    Kristensson, Krister
    Karolinska Institutet.
    Juliano, Sharon L.
    Uniformed Serv Univ Hlth Sci, USA.
    Lutwama, Julius J.
    Uganda Virus Res Inst, Uganda.
    Emerging Viral Infections in Sub-Saharan Africa and the Developing Nervous System: A Mini Review2018In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 82Article, review/survey (Refereed)
    Abstract [en]

    The global public health concern is heightened over the increasing number of emerging viruses, i.e., newly discovered or previously known that have expanded into new geographical zones. These viruses challenge the health-care systems in sub-Saharan Africa (SSA) countries from which several of them have originated and been transmitted by insects worldwide. Some of these viruses are neuroinvasive, but have been relatively neglected by neuroscientists. They may provide experiments by nature to give a time window for exposure to a new virus within sizeable, previously non-infected human populations, which, for instance, enables studies on potential long-term or late-onset effects on the developing nervous system. Here, we briefly summarize studies on the developing brain by West Nile, Zika, and Chikungunya viruses, which are mosquito-borne and have spread worldwide out of SSA. They can all be neuroinvasive, but their effects vary from malformations caused by prenatal infections to cognitive disturbances following perinatal or later infections. We also highlight Ebola virus, which can leave surviving children with psychiatric disturbances and cause persistent infections in the non-human primate brain. Greater awareness within the neuroscience community is needed to emphasize the menace evoked by these emerging viruses to the developing brain. In particular, frontline neuroscience research should include neuropediatric follow-up studies in the field on long-term or late-onset cognitive and behavior disturbances or neuropsychiatric disorders. Studies on pathogenetic mechanisms for viral-induced perturbations of brain maturation should be extended to the vulnerable periods when neurocircuit formations are at peaks during infancy and early childhood.

  • 32.
    Knabl, Ludwig
    et al.
    Medical University of Innsbruck, Austria.
    Berktold, Michael
    Medical University of Innsbruck, Austria.
    Hamad, Osama
    Uppsala university, Sweden.
    Fromell, Karin
    Uppsala university, Sweden.
    Chatterjee, Sneha
    Medical University of Innsbruck, Austria.
    Speth, Cornelia
    Medical University of Innsbruck, Austria.
    Talasz, Herbert
    Medical University of Innsbruck, Austria.
    Lindner, Katharina
    Medical University of Innsbruck, Austria.
    Hermann, Martin
    Medical University of Innsbruck, Austria.
    Nilsson Ekdahl, Kristina
    Uppsala university, Sweden.
    Nilsson, Bo
    Uppsala university, Sweden.
    Streif, Werner
    Medical University of Innsbruck, Austria.
    Martini, Judith
    Medical University of Innsbruck, Austria.
    Würzner, Reinhard
    Medical University of Innsbruck, Austria.
    Orth-Höller, Dorothe
    Medical University of Innsbruck, Austria.
    Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets2018In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 308, no 7, p. 969-976Article in journal (Refereed)
    Abstract [en]

    Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombiseems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism.

    The present study investigated the effect of Stx2a on plasmatic coagulation and platelets. Binding studies were initially performed with ELISA and co-immunoprecipitation and supported by quartz crystal microbalance with dissipation monitoring (QCM-D). Antithrombin (AT) activity was measured using the automated BCS XP® system. ROTEM® was used for functional coagulation testing. Platelet binding and activation was studied with FACS and light-transmission aggregometry.

    We found binding of Stx2a to AT, an important inhibitor of blood coagulation, but only a mild albeit significant reduction of AT activity against FXa in the presence of Stx2a. QCM-D analysis also showed binding of Stx2a to heparin and an impaired binding of AT to Stx2a-bound heparin. ROTEM® using Stx2a-treated platelet-poor plasma revealed a significant, but only moderate shortening of clotting time. Neither binding nor activation of platelets by Stx2a could be demonstrated.

    In summary, data of this study suggest that Stx2a binds to AT, but does not induce major effects on plasmatic coagulation. In addition, no interaction with platelets occurred. The well-known non-beneficial administration of heparin in eHUS patients could be explained by the interaction of Stx2a with heparin.

  • 33.
    Lindberg, A. Michael
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Johansson, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Andersson, Anne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Echovirus 5: infectious transcripts and complete nucleotide sequence from uncloned cDNA1999In: Virus Research, ISSN 0168-1702, Vol. 59, no 1, p. 75-87Article in journal (Refereed)
    Abstract [en]

    Echovirus 5 (EV5) may be isolated from various neurological and exanthematic diseases. To determine the relationship of EV5 to other enteroviruses and for studies of its interactions with the target cell, the complete nucleotide sequence of EV5 was determined. Three overlapping fragments, collectively representing the complete genome, were amplified with RT–PCR and sequenced. Analysis of the EV5 sequence revealed a typical enterovirus-like organization of the genome. To verify that the cDNA generated sequence was derived from infectious viruses, complete EV5 genomes were amplified in one amplicon by long distance PCR. Transfection of in vitro transcribed RNA from these amplicons into cell cultures resulted in replicating EV5. Comparison of the overall nucleotide and amino acid sequences demonstrates that EV5 can be regarded as a coxsackievirus B-like enterovirus. Variable sequences between EV5 and the well characterized coxsackievirus B3 (CVB3) are for the most part observed for amino acid residues that correspond to exposed sequences in the CVB3 capsid. This observation indicates that the reported EV5 strain recently diverged from group B coxsackieviruses.

  • 34.
    Lindberg, A Michael
    et al.
    Department of Medical Genetics and Microbiology, Biomedical Center, University of Uppsala.
    Stålhanske, POK
    Pettersson, U.
    Genome of Coxsackievirus B31987In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 156, no 1, p. 50-63Article in journal (Refereed)
    Abstract [en]

    The entire nucleotide sequence of the coxsackievirus B3 strain Nancy (CB3) genome has been determined from cDNA. The genome is 7396 nucleotides long, and encodes a 2185 amino acid long polyprotein. It exhibits the same gene organization as other enterovirus genomes. A detailed comparison was carried out between the proteins encoded by the CB3 and poliovirus type 1 strain Mahoney (PVI) genomes. The genes encoding the VPg polypeptide and the viral polymerase are the most conserved regions. The structural polypeptides VP1, VP2, and VP3 are less well conserved although proline and tryptophan residues frequently are found in identical positions. The VP1 protein of CB3 shows a particularly limited homology in those regions which have been found to induce neutralizing antibodies against PV1. The 5′ noncoding region of CB3 is closely related to that of PV1, with regard to both length and sequence organization, whereas the 3′ noncoding region of CB3 exhibits some unique features. 

  • 35. Lindberg, Michael
    et al.
    Johansson, Susanne
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Phylogenetic analysis of Ljungan virus and A-2 plaque virus, new members of the Picornaviridae2002In: Virus Research, ISSN 0168-1702, Vol. 85, no 1, p. 61-70Article in journal (Refereed)
  • 36. Lindberg, Michael
    et al.
    Polacek, Charlotta
    Johansson, Susanna
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Amplification and cloning of complete enterovirus genomes by long distance PCR1997In: Journal of Virological Methods, ISSN 0166-0934, Vol. 65, no 2, p. 191-199Article in journal (Refereed)
  • 37.
    Lövström, Tora
    University of Kalmar, School of Pure and Applied Natural Sciences.
    An epidemiological study of Swedish Campylobacter jejuni isolates from humans and broilers using multilocus sequence typing2009Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    Campylobacter jejuni is the main cause of bacterial diarrhoeal illness in developed countries, with ~7000 cases being reported each year in Sweden. C. jejuni has received growing attention since it’s recognition as a human pathogen in the 1970s, but its epidemiology is complex and much still remains unknown. There are several potential reservoirs for C. jejuni, including environmental sources as water and soil, wild and domesticated animals, particularly poultry, but also other livestock and pets. In this study 348 Swedish C. jejuni isolates from the year 2000 from humans (n = 164) and broilers (n = 184) were characterized with multilocus sequence typing (MLST) with the aim of comparing the population structures and diversity of C. jejuni between isolates from the two hosts. MLST is a method for characterization of bacterial isolates that indexes the variation in DNA sequence of multiple protein encoding housekeeping genes. A secondary aim in this study was to compare populations of C. jejuni from 11 subgroups of isolates based on location of the sampling. The overlap between the populations was analyzed numerically based on genotypes detected and with analysis of phylogeny, gene flow and molecular variation. It was shown that the population structure of C. jejuni isolates from broilers and humans show a high degree of similarity, supporting broilers as an important source of human infection. However, even though the population structure of human and broiler C. jejuni were almost genetically indistinguishable other sources of C. jejuni infections in humans cannot be ruled out since the same genotypes can be found in other sources as well. Analysis of the 11 subgroups suggested that there may be a difference in populations infecting humans in different Swedish regions, and between populations of C. jejuni in broilers from different slaughterhouses. But this could be a result of chance since most of the subgroups were small. Future studies to improve the understanding of C. jejuni epidemiology, for which MLST has proven itself as a valid method, is important to develop control strategies to prevent infection with this common cause of diarrhoeal illness.

  • 38.
    Newcombe, Nicole G
    et al.
    University of Newcastle.
    Andersson, Per
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Johansson, E Susanne
    University of Newcastle.
    Au, Gough G
    University of Newcastle.
    Lindberg, A. Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Barry, Richard D
    University of Newcastle.
    Shafren, Darren R
    University of Newcastle.
    Cellular receptor interactions of C-cluster human group A coxsackieviruses.2003In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 84, no Pt 11, p. 3041-3050Article in journal (Refereed)
    Abstract [en]

    The cellular receptor complex of coxsackievirus A21 (CVA21), a C-cluster human enterovirus, is formed by the subtle interaction of individual cellular receptors, decay accelerating factor (DAF) and intercellular adhesion molecule-1 (ICAM-1). In this receptor complex, DAF functions in the membrane sequestration of the virus, while the role of ICAM-1 is as the functional cellular internalization receptor. However, despite the elucidation of the CVA21-cell receptor interactions, there have been few definite investigations into cellular receptor usage of other coxsackie A viruses (CVAs) belonging to the C-cluster. In the present study, radiolabelled virus-binding assays demonstrated that CVA13, -15, -18 and -20, a subset of the human enterovirus C-cluster, bind directly to surface-expressed ICAM-1, but not to surface-expressed DAF. Furthermore, lytic infection of ICAM-1-expressing rhabdomyosarcoma (RD) cells by this C-cluster subset of viruses was inhibited by specific ICAM-1 monoclonal antibody blockade, except for that of CVA20. Despite possessing ICAM-1-binding capabilities, CVA20 employed an as yet unidentified internalization receptor for cell entry and subsequent productive lytic infection of ICAM-1-negative RD cells. In a further example of C-cluster cellular receptor heterogeneity, CVA13 exhibited significant binding to the surface of CHO cells expressing neither DAF nor ICAM-1. Despite a common receptor usage of ICAM-1 by this subset of C-cluster CVAs, the amino acid residues postulated to represent the ICAM-1-receptor footprint were not conserved.

  • 39.
    Newcombe, Nicole G
    et al.
    University of Newcastle.
    Johansson, E Susanne
    University of Newcastle.
    Au, Gough
    University of Newcastle.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Barry, Richard D
    University of Newcastle.
    Shafren, Darren R
    University of Newcastle.
    Enterovirus capsid interactions with decay-accelerating factor mediate lytic cell infection2004In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 78, no 3, p. 1431-9Article in journal (Refereed)
    Abstract [en]

    The cellular receptor usage of numerous human enteroviruses can differ significantly between low-cell-culture-passaged clinical isolates and highly laboratory-passaged prototype strains. The prototype strain of coxsackievirus A21 (CVA21) displays a dual-receptor specificity as determined with a receptor complex consisting of decay-accelerating factor (DAF) and intercellular adhesion molecule 1 (ICAM-1). In this study, the cellular receptor interactions of low-cell-passage CVA21 clinical isolates with respect to their interactions with cell surface-expressed DAF and ICAM-1 were compared to those of the CVA21 prototype (Kuykendall) strain. Dual-receptor usage of DAF and ICAM-1 by CVA21 clinical isolates was confirmed by cell transfection and radiolabeled binding assays. The cellular attachment of clinical and prototype CVA21 strains to cells that coexpressed DAF and ICAM-1 was not additive compared to the viral binding to cells expressing one or other receptor. In fact, the binding data suggest there is an inhibition of CVA21 cellular attachment in environments where high-level coexpression of both DAF and ICAM-1 occurs. Antibody cross-linking of DAF rendered cells susceptible to lytic infection by the CVA21 clinical isolates. In a novel finding, three clinical isolates could, to various degrees, infect and lyse DAF-expressing cells in the absence of DAF-antibody cross-linking and ICAM-1 expression. Sequence analysis of the P1 region of clinical and prototype virus genomes identified a number of coding changes that may contribute to the observed enhanced DAF usage phenotype of the clinical CVA21 isolates. None of the amino acid changes was located in the previously postulated ICAM-1 footprint, a receptor-binding environment that was conserved on the capsid surface of all CVA21 clinical isolates. Taken together, the data suggest that community-circulating strains of CVA21 can infect target cells expressing either ICAM-1 or DAF alone and that such interactions extend tissue tropism and impact directly on viral pathogenesis.

  • 40.
    Nilsson Ekdahl, Kristina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Huang, Shan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nilsson, Bo
    Uppsala University.
    Teramura, Yuji
    Uppsala University;The University of Tokyo, Japan.
    Complement inhibition in biomaterial- and biosurface-induced thromboinflammation2016In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 28, no 3, p. 268-277Article in journal (Refereed)
    Abstract [en]

    Therapeutic medicine today includes a vast number of procedures involving the use of biomaterials, transplantation of therapeutic cells or cell clusters, as well as of solid organs. These treatment modalities are obviously of great benefit to the patient, but also present a great challenge to the innate immune system, since they involve direct exposure of non-biological materials, cells of non-hematological origin as well as endothelial cells, damaged by ischemia-perfusion in solid organs to proteins and cells in the blood. The result of such an exposure may be an inappropriate activation of the complement and contact/kallikrein systems, which produce mediators capable of triggering the platelets and PMNs and monocytes, which can ultimately result in thrombotic and inflammatory (i.e., a thrombo-inflammatory) response to the treatment modality. In this concept review, we give an overview of the mechanisms of recognition within the innate immunity system, with the aim to identify suitable points for intervention. Finally, we discuss emerging and promising techniques for surface modification of biomaterials and cells with specific inhibitors in order to diminish thromboinflammation and improve clinical outcome.

  • 41.
    Nordström, F
    et al.
    Center for Chemistry and Chemical Engineering, Department of Biotechnology, Lund University, Lund, Sweden.
    Terrazas, E
    Center for Chemistry and Chemical Engineering, Department of Biotechnology, Lund University, Lund, Sweden.
    Welander, Ulrika
    Växjö University, Faculty of Mathematics/Science/Technology, School of Technology and Design. Center for Chemistry and Chemical Engineering, Department of Biotechnology, Lund University, Lund, Sweden.
    Decolorization of a mixture of textile dyes using Bjerkandera sp. BOL 132008In: Environmental technology, ISSN 0959-3330, E-ISSN 1479-487X, Vol. 29, no 8, p. 921-929Article in journal (Refereed)
    Abstract [en]

    The white-rot fungus Bjerkandera sp. BOL 13 was evaluated regarding decolorization of four textile dyes Reactive blue 21, Reactive black 5, Reactive orange 13 and Reactive yellow 206. Experiments were performed in batch and continuous modes. The total dye concentration in all experimtents was 100 mg/l. The results of the batch experiments showed that the fungus decolorized all dyes but at different rates. There was, however, an increase in the ultraviolet (UV) absorbance when a medium with a low concentration of nitrogen was used. No increase in UV range was observed when the nitrogen concentration was increased. A continuous experiment was performed to study the decolorization of a mixture of three of the dyes Reactive blue 21, Reactive black 5 and Reactive orange 13. Scanning of inlet and outlet samples showed that the absorbance at the peaks in the visible range decreased by 60-66%. The UV absorbance of the outlet increased during the first days of operation after which it decreased again to reach the same level as the inlet. The hydraulic retention time in the reactor was 3 days. The medium containing the higher nitrogen concentration was used in the continuous experiment.

  • 42.
    Olofsson, Jenny
    et al.
    Uppsala University.
    Griekspoor, Petra
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Olsen, Björn
    Uppsala University.
    Ellström, Patrik
    Uppsala University.
    Axelsson Olsson, Diana
    Linnaeus University, Faculty of Health and Life Sciences, Department of Medicine and Optometry. Uppsala University.
    The abundant free-living amoeba, Acanthamoeba polyphaga, increases the survival of Campylobacter jejuni in milk and orange juice2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 28675Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Campylobacter jejuni is a common cause of human bacterial diarrhea in most parts of the world. Most C. jejuni infections are acquired from contaminated poultry, milk, and water. Due to health care costs and human suffering, it is important to identify all possible sources of infection. Unpasteurized milk has been associated with several outbreaks of C. jejuni infection. Campylobacter has been identified on fresh fruit, and other gastrointestinal pathogens such as Salmonella, E. coli O157:H7 and Cryptosporidium have been involved in fruit juice outbreaks. C. jejuni is sensitive to the acidic environment of fruit juice, but co-cultures with the amoeba, Acanthamoeba polyphaga, have previously been shown to protect C. jejuni at low pH.

    METHODS: To study the influence of A. polyphaga on the survival of C. jejuni in milk and juice, the bacteria were incubated in the two products at room temperature and at 4°C with the following treatments: A) C. jejuni preincubated with A. polyphaga before the addition of product, B) C. jejuni mixed with A. polyphaga after the addition of product, and C) C. jejuni in product without A. polyphaga. Bacterial survival was assessed by colony counts on blood agar plates.

    RESULTS: Co-culture with A. polyphaga prolonged the C. jejuni survival both in milk and juice. The effect of co-culture was most pronounced in juice stored at room temperature. On the other hand, A. polyphaga did not have any effect on C. jejuni survival during pasteurization of milk or orange juice, indicating that this is a good method for eliminating C. jejuni in these products.

    CONCLUSION: Amoebae-associated C. jejuni in milk and juice might cause C. jejuni infections.

  • 43.
    Orozovic, Goran
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Resistance to neuraminidase inhibitors in influenza A virus isolated from mallards2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Influenza A virus belongs to the Orothomyxoviridae family of viruses and is one of the most common pathogens that cause infections of the respiratory tract. The aim of this thesis was to investigate if neuraminidase inhibitor (NAI) Tamiflu® (oseltamivir, OC) and Relenza® (zanamivir, ZA) - related resistance mutations exist in the neuraminidase (NA) gene of viruses collected from wild birds.

    A new set of degenerate primers was designed for the sequencing procedure, which resulted in a protocol that reduced time and costs of NA sequencing. This protocol was employed for subtyping of 120 NA genes (i.e. influenza viruses). Altogether, 230 NA sequences from avian influenza viruses originating from wild mallards (Ottenby, Sweden) were scanned for NAI-related mutations together with 5,490 avian, 379 swine and 122 environmental NA sequences from the NCBI dataset. The screening showed a distinction between the numbers of mutants found in avian virus sequences derived from NCBI (2.4%) as compared to virus sequences form mallards (6.5%). This is the first report of NAI resistance mutations in viruses isolated from wild birds.

    The mutants carrying NAI resistance-related and resistance-unrelated mutations were screened using NA inhibition assay (NAIA) with ZA and OC inhibitors. The majority of mutations assayed showed IC50 values indicating an inhibitor sensitive phenotype. One H12N3 mutant showed a cross-resistant phenotype, i.e. insensitive to both ZA and OC treatment. Protein structure homology-modeling indicated that this cross-resistance might be associated to a D151K mutation, possibly supported by changes in NA residue 149, 150, 152 and 153. In addition, an OC resistance-related emergence of H274Y mutants was revealed in an experimental set up where mallard ducks, subjected to different concentrations of OC ( 0.28, 3.5 and 280 nM)  in their water pool, were infected with avian H1N1 virus.

    In conclusion, this thesis provides new insights into the field of NAI resistance in avian influenza virus as well as indicating the evolutionary forces modern drug design has to confront. This thesis also emphasizes the importance of a continuous search for new means of protecting the human population from this potentially devastating pathogen. 

  • 44.
    Orozovic, Goran
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Orozovic, Kanita
    Järhult, Josef
    Tolf, Conny
    Latore-Margalef, Neus
    Lennerstrand, Johan
    Olsen, Björn
    Detection of Oseltamivir-and Zanamivir-Resistant Influenza A (H12N3) Virus from Wild Mallards in SwedenManuscript (preprint) (Other academic)
    Abstract [en]

    Resistance to neuraminidase inhibitors (NAIs) is a growing problem in battle against influenza A virus. However, little is known about the resistance of viruses isolated from dabbling ducks, the natural reservoir of the virus. To date, no low-pathogenic avian influenza (LPAI) virus that is resistant to NAIs has been detected. The aim of this study is to investigate mallard isolates of influenza A virus previously identified to carry oseltamivir carboxylate (OC)- or zanamivir (ZA)-related resistance mutations. In this work, 22 viruses belonging to the N1, N3, N6 and N9 subtypes were analyzed using a colorimetric NA inhibition assay. The R118K mutation was the most recurrent, as it was observed in all subtypes except for N6. IC50 values confirmed the differences in sensitivity to OC or ZA observed in the N1 and N2 groups of NAs. Furthermore, both negative controls (NC) in the N6 and one NC in the N9 subtype were less sensitive to ZA than were genotypically related mutants of the respective subtypes. One H12N3 strain (80087 isolate) was cross-resistant, with an IC50 of >104 nM. This virus carried D151K and R156K mutations that were not associated with NAI resistance. Analyses of the 3D structure of NA indicated that the NAI-resistant phenotype that retained NA catalytic activity was likely to be due to the D151K mutation. However, the residues occupying positions 149, 150 (part of the 150 loop) and 153 may have contributed to this resistance. Other possible factors included the presence of the 150 cavity, the nature of the substrate (anchored or unanchored) and the interaction of the ligand with the active site. These results demonstrate that NAI-resistant viruses exist in LPAI and highlight the importance of monitoring influenza A viruses in wild birds, as these viruses can be transmitted to humans and can thus become part of a human-adapted influenza virus with pandemic potential.

  • 45.
    Orozovic, Goran
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. Uppsala University.
    Orozovic, Kanita
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lennerstrand, Johan
    Uppsala University.
    Olsen, Björn
    Uppsala University.
    Detection of Resistance Mutations to Antivirals Oseltamivir and Zanamivir in Avian Influenza A Viruses Isolated from Wild Birds2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, article id e16028Article in journal (Refereed)
    Abstract [en]

    The neuraminidase (NA) inhibitors oseltamivir and zanamivir are the first-line of defense against potentially fatal variants of influenza A pandemic strains. However, if resistant virus strains start to arise easily or at a high frequency, a new anti-influenza strategy will be necessary. This study aimed to investigate if and to what extent NA inhibitor–resistant mutants exist in the wild population of influenza A viruses that inhabit wild birds. NA sequences of all NA subtypes available from 5490 avian, 379 swine and 122 environmental isolates were extracted from NCBI databases. In addition, a dataset containing 230 virus isolates from mallard collected at Ottenby Bird Observatory (Öland, Sweden) was analyzed. Isolated NA RNA fragments from Ottenby were transformed to cDNA by RT-PCR, which was followed by sequencing. The analysis of genotypic profiles for NAs from both data sets in regard to antiviral resistance mutations was performed using bioinformatics tools. All 6221 sequences were scanned for oseltamivir- (I117V, E119V, D198N, I222V, H274Y, R292K, N294S and I314V) and zanamivir-related mutations (V116A, R118K, E119G/A/D, Q136K, D151E, R152K, R224K, E276D, R292K and R371K). Of the sequences from the avian NCBI dataset, 132 (2.4%) carried at least one, or in two cases even two and three, NA inhibitor resistance mutations. Swine and environmental isolates from the same data set had 18 (4.75%) and one (0.82%) mutant, respectively, with at least one mutation. The Ottenby sequences carried at least one mutation in 15 cases (6.52%). Therefore, resistant strains were more frequently found in Ottenby samples than in NCBI data sets. However, it is still uncertain if these mutations are the result of natural variations in the viruses or if they are induced by the selective pressure of xenobiotics (e.g., oseltamivir, zanamivir).

  • 46.
    Otterdal, K
    et al.
    Oslo University Hospital Rikshospitalet, Norway.
    Portillo, A
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Astrup, E
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Ludviksen, J K
    Nordland Hospital, Norway.
    Schjalm, C
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Raoult, D
    Université de la Mediterranée, France.
    Olano, J P
    University of Texas Medical Branch, USA.
    Halvorsen, B
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Oteo, J A
    Hospital San Pedro-Center of Biomedical Research from La Rioja (CIBIR), Spain.
    Aukrust, P
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Mollnes, T E
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway ; Nordland Hospital, Norway ; University of Tromsø, Norway ; Norwegian University of Science and Technology, Norway.
    Nilsson, Per H.
    Oslo University Hospital Rikshospitalet, Norway ; University of Oslo, Norway.
    Rickettsia conorii is a potent complement activator in vivo and combined inhibition of complement and CD14 is required for attenuation of the cytokine response ex vivo.2016In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 22, no 8, p. 734.e1-734.e6Article in journal (Refereed)
    Abstract [en]

    Mediterranean spotted fever caused by Rickettsia conorii is a potentially lethal disease characterized by vascular inflammation affecting multiple organs. Studies of R. conorii so far have focused on activation of inflammatory cells and their release of inflammatory cytokines, but complement activation has not been investigated in R. conorii-infected patients. Here, we performed a comprehensive analysis of complement activation markers and the soluble cross-talking co-receptor CD14 (sCD14) in plasma from R. conorii-infected patients. The clinical data were supplemented with ex vivo experiments where the cytokine response was characterized in human whole blood stimulated with R. conorii. Complement activation markers at the level of C3 (C3bc, C3bBbP) and terminal pathway activation (sC5b-9), as well as sCD14, were markedly elevated (p <0.01 for all), and closely correlated (p <0.05 for all), in patients at admission compared with healthy matched controls. All tested markers were significantly reduced to baseline values at time of follow up. Rickettsia conorii incubated in human whole blood was shown to trigger complement activation accompanied by release of the inflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8 and tumour necrosis factor. Whereas inhibition of either C3 or CD14 had only a minor effect on released cytokines, combined inhibition of C3 and CD14 resulted in significant reduction, virtually to baseline levels, of the four cytokines (p <0.05 for all). Our data show that complement is markedly activated upon R. conorii infection and complement activation is, together with CD14, responsible for a major part of the cytokine response induced by R. conorii in human whole blood.

  • 47.
    Polacek, Charlotta
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Ekström, Jens-Ola
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lundgren, Anneli
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Cytolytic replication of coxsackievirus B2 in CAR-deficient rhabdomyosarcoma cells.2005In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 113, no 2, p. 107-15Article in journal (Refereed)
    Abstract [en]

    The six coxsackievirus B serotypes (CVB1-6) use the coxsackie- and adenovirus receptor (CAR) for host cell entry. Four of these serotypes, CVB1, 3, 5 and 6, have also shown the capacity to replicate and cause cytolysis in rhabdomyosarcoma (RD) cells, a CAR-deficient cell line. This extended tropism has been associated with an acquired ability to bind decay accelerating factor (DAF). In this study, we have adapted the CVB2 prototype strain Ohio-1 (CVB2/O) to replicate in RD cells. Two types of infection were identified: (I) an enterovirus-typical, lytic infection, and (II) a non-lytic infection. Both CVB2/O-RD variants retained the prototype-ability to cause cytopathic effect in HeLa cells using CAR as receptor. Phenotypic and genotypic changes in the CVB2/O-RD-variants were determined and compared to the prototype cultured in HeLa cells. Inhibition studies using antibodies against CAR and DAF revealed a maintained ability of the CVB2/O-RD-variants to bind CAR, but no binding to DAF was observed. In addition, neither the prototype nor the CVB2/O-RD-variants were able to cause hemagglutination in human red blood cells, an enterovirus feature associated with affinity for DAF. Sequence analysis of the CVB2/O-RD-variants showed acquired mutations in the capsid region, suggesting extended receptor usage towards an alternative, yet unidentified, receptor for CVB2.

  • 48. Stålhanske, P.O.K.
    et al.
    Lindberg, A Michael
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Pettersson, U.
    Replicase Gene of Coxsackievirus B31984In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 51, no 3, p. 742-746Article in journal (Refereed)
    Abstract [en]

    A cDNA copy covering two-thirds of the coxsackievirus B3 genomewas cloned in the PstI site of the pBR322 vector. A nucleotidesequence containing the gene for the viral replicase and the3' noncoding region of the coxsackievirus B3 genome was determined.The predicted amino acid sequence of the coxsackievirus B3 replicasewas shown to be remarkably similar to that of the poliovirus1 replicase. The 3' noncoding region, in contrast, was onlyweakly homologous to the poliovirus 1 sequence but showed aclose relationship to the sequence of swine vesicular diseasevirus, a variant of coxsackievirus B5. A 13-nucleotide-longsegment located near the polyadenylic acid junction is conservedin several members of the enterovirus group and may thus servean important function during replication of viral RNA. 

  • 49.
    Svensson, Lovisa
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Nitric oxide and bacteria-host interactions in Escherichia coli urinary tract infection2008Doctoral thesis, comprehensive summary (Other academic)
  • 50.
    Svensson, Lovisa
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Mohlin, Camilla
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Persson, Katarina
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Upregulation of Heme Oxygenase-1 as a Host Mechanism for Protection Against Nitric Oxide–induced Damage in Human Renal Epithelial Cells2009In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 73, no 5, p. 749-753Article in journal (Refereed)
    Abstract [en]

    ObjectivesTo examine whether urinary tract infection–associated stimuli could regulate heme oxygenase-1 (HO-1) expression and to asses the significance of HO-1 in protecting urinary tract epithelial cells against nitric oxide (NO)-induced damage.

    MethodsHeme oxygenase-1 expression was investigated in the human renal epithelial cell line A498 in response to the uropathogenic Escherichia coli (UPEC) strain IA2, the NO-donor DETA/NONOate (DETA/NO), and proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α, and interferon-γ) using reverse transcriptase polymerase chain reaction and Western blot analysis. Cell viability was examined by the trypan blue exclusion test and light microscopy.

    ResultsThe HO-1 inducer hemin and DETA/NO increased HO-1 expression in A498 cells, and glutathione depletion further increased HO-1 expression in response to DETA/NO and hemin. Stimulation with a UPEC strain or cytokines did not upregulate HO-1 expression. The cytokines induced inducible NO synthase expression and caused an increase in nitrite production. Hemin significantly decreased cytokine-induced NO production (P <0.001). DETA/NO decreased the cell viability by approximately 75%, but hemin was able to attenuate DETA/NO-induced cell damage.

    ConclusionsThe expression of HO-1 increased in human renal epithelial cells in response to NO, and the expression was further enhanced in glutathione-depleted cells. The bacteria per se or proinflammatory cytokines were not able to upregulate HO-1. Heme oxygenase-1 protects the cells against NO by feedback inhibition of NO production and by decreasing cell damage.

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