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The Evolution of Innate Immune Genes: Purifying and Balancing Selection on beta-Defensins in Waterfowl
Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. (Ctr Ecol & Evolut Microbial Model Syst EEMiS)ORCID iD: 0000-0003-2849-1094
Lund University.
Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. (Ctr Ecol & Evolut Microbial Model Syst EEMiS)
Univ Konstanz, Germany;Max Planck Inst Ornithology, Germany.
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2016 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 33, no 12, p. 3075-3087Article in journal (Refereed) Published
Abstract [en]

In disease dynamics, high immune gene diversity can confer a selective advantage to hosts in the face of a rapidly evolving and diverse pathogen fauna. This is supported empirically for genes involved in pathogen recognition and signalling. In contrast, effector genes involved in pathogen clearance may be more constrained. beta-Defensins are innate immune effector genes; their main mode of action is via disruption of microbial membranes. Here, five beta-defensin genes were characterized in mallards (Anas platyrhynchos) and other waterfowl; key reservoir species for many zoonotic diseases. All five genes showed remarkably low diversity at the individual-, population-, and species-level. Furthermore, there was widespread sharing of identical alleles across species divides. Thus, specific beta-defensin alleles were maintained not only spatially but also over long temporal scales, with many amino acid residues being fixed across all species investigated. Purifying selection to maintain individual, highly efficacious alleles was the primary evolutionary driver of these genes in waterfowl. However, we also found evidence for balancing selection acting on the most recently duplicated beta-defensin gene (AvBD3b). For this gene, we found that amino acid replacements were more likely to be radical changes, suggesting that duplication of beta-defensin genes allows exploration of wider functional space. Structural conservation to maintain function appears to be crucial for avian beta-defensin effector molecules, resulting in low tolerance for new allelic variants. This contrasts with other types of innate immune genes, such as receptor and signalling molecules, where balancing selection to maintain allelic diversity has been shown to be a strong evolutionary force.

Place, publisher, year, edition, pages
2016. Vol. 33, no 12, p. 3075-3087
Keywords [en]
Antimicrobial peptides, host defense peptides, ecoimmunology, avian immune system, host-pathogen dynamics
National Category
Evolutionary Biology Immunology
Research subject
Ecology, Evolutionary Biology; Biomedical Sciences, Immunology
Identifiers
URN: urn:nbn:se:lnu:diva-59004DOI: 10.1093/molbev/msw167ISI: 000387925300005Scopus ID: 2-s2.0-85016214902OAI: oai:DiVA.org:lnu-59004DiVA, id: diva2:1056672
Available from: 2016-12-15 Created: 2016-12-14 Last updated: 2020-02-07Bibliographically approved
In thesis
1. Eco-immunological studies of innate immunity in Mallards (Anas platyrhynchos)
Open this publication in new window or tab >>Eco-immunological studies of innate immunity in Mallards (Anas platyrhynchos)
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis comprises two sections, both of which explore eco-immunology of the innate immune system of mallards (Anas platyrhynchos). The innate immune system serves a pivotal role as the first line of defense against invading pathogens, and is comprised of physical and chemical barriers. Its main function is to inhibit and/or eliminate the pathogenic microorganisms while minimizing collateral damage to host cells.

The first section investigates the allelic variation and selective forces acting on five avian β-defensins (AvBD) genes. Showing that purifying selection is the predominant selective force, although one gene AvBD3b, appeared to be subject to balancing selection. Moreover, the solution structure of the AvBD3b peptide was solved in this work, revealing that it contains a typical β-defensin fold with three β-sheets. Linear and folded AvBD3b peptides were shown to exhibit similar antibacterial properties, indicating that the tertiary structure was not the primary determinant of antimicrobial activity. Moreover, testing the antimicrobial activity of synthetic AvBD peptides showed that they mostly had higher activity against Gram-negative than Gram-positive bacteria.

The second section investigates expression of two innate immune genes during avian influenza virus infection. Data quality in gene expression studies depends, in part, on the stability of the reference genes (RGs) used to normalize expression levels, meaning putative RGs must be validated prior to use. Eleven potential mallard RGs were tested and it was found that the stability varied across different tissue types, highlighting the importance of correct RG selection for the specific experimental conditions. Optimal RGs were then used in a gene expression study of retinoic acid inducible gene 1 (RIG-I) and myxovirus resistant gene (Mx) in mallards during a low pathogenic avian influenza (LPAI) infection. Upregulation of both genes was rapid and transient, returning back to basal levels two days post infection across most of the five tissue types analyzed.

This thesis provides new insights into the tertiary structure and antimicrobial activity of AvBDs, and how this relates to selective pressures exerted in natural populations. It also highlights the importance of RGs validation, and confirms that RIG-I and Mx are involved in the early stages of the mallard immune response to LPAI infection.

Abstract [sv]

Den här avhandlingen består av två delar, vilka fokuserar på olika delar av det medfödda immunförsvaret hos gräsand (Anas platyrhynchos). Det medfödda immunförsvaret består av fysiska och kemiska barriärer vars uppgift är att hindra patogener att infektera kroppens celler, och att vid infektion eliminera dem.

Första delen undersöker allelvariation och selektion hos generna för fem olika β-defensiner (AvBD) hos gräsand och andra änder. Studierna visade att stabiliserande urval är den dominerande selektionskraften för dessa gener utom för AvBD3b, som var föremål för balanserande selektion. Den tredimensionella strukturen för AvBD3b bestämdes och uppvisade en generell β-defensinstruktur innehållande tre β-flak. Syntetiserade linjära och veckade AvBD3b-peptider hade liknande antibakteriella egenskaper, vilket antyder att den tredimensionella strukturen inte är avgörande för den antibakteriella funktionen. Den antimikrobiella aktiviteten hos ytterligare fem AvBD-peptider testades och uppvisade en högre aktivitet mot Gram-negativa än mot Gram-positiva bakterier.

Andra delen undersöker genuttryck av två immunförsvarsgener vid fågelinfluensainfektion. Vid genuttrycksstudier är resultatet till viss del beroende av stabiliteten hos de referensgener (RG) som används för normalisering av data. Därför behöver dessa validerades innan användning vid genuttrycksstudier. Elva potentiella RG testades och uppvisade varierande uttryck i olika vävnader hos gräsand, vilket visar vikten av att testa stabiliteten för den specifika experimentuppställningen. Baserat på dessa resultat användes referensgenerna i ett experiment där genuttrycket av retinoic acid inducible gene 1 (RIG-I) och myxovirus resistance gene (Mx) undersöktes i gräsänder infekterade med fågelinfluensavirus. Båda generna uppvisade en snabb och övergående uppreglering, där genuttrycket återgick till bakgrundsnivåer två dagar efter infektionsstart i nästan alla analyserade vävnader.

Denna avhandling ger nya insikter om genetisk diversitet och evolution hos AvBD-gener i gräsand. Den tredimensionella strukturen av AvBD3b bidrar till ökad kunskap om AvBD-strukturer då endast några få defensinstrukturer från fåglar tidigare bestämts. Avhandlingen visar även på vikten av att undersöka stabiliteten hos potentiella referensgener för att få pålitliga resultat vid expressionsstudier samt att generna RIG-I och Mx är involverade under den tidiga immunresponsen vid fågelinfluensavirusinfektion i gräsänder.

Place, publisher, year, edition, pages
Växjö: Linnaeus University Press, 2020. p. 64
Series
Linnaeus University Dissertations ; 376/2020
Keywords
Avian β-defensins (AvBDs), Avian gene expression, Host-pathogen interactions, Innate immunity, Mallard (Anas platyrhynchos), Myxovirus resistance gene (Mx), Retinoic acid inducible gene 1 (RIG-I), Avian β-defensins (AvBD), Genuttryck, Gräsand (Anas platyrhynchos), Immunförsvar, Immungener, Myxovirus resistant gene (Mx), Patogen, Retinoic acid inducible gene 1 (RIG-I)
National Category
Ecology
Identifiers
urn:nbn:se:lnu:diva-91986 (URN)978-91-89081-33-8 (ISBN)978-91-89081-34-5 (ISBN)
Public defence
2020-02-28, Fullriggaren (Ma135), Kalmar, 09:30 (English)
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Supervisors
Available from: 2020-03-03 Created: 2020-02-07 Last updated: 2020-05-13Bibliographically approved

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Chapman, Joanne R.Helin, Anu S.Waldenström, Jonas

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