Coinfection Dynamics and Host Restriction in Influenza A Virus Infection Open Access

Abstract

Genetic exchange between coinfecting influenza A viruses can drive viral evolution and is particularly important in facilitating adaptation to new host species. Thus, we investigated how coinfection and host restriction impact IAV replication in novel hosts. We have previously demonstrated that IAVs benefit from virus-virus interactions during homologous coinfection, indicating an intrinsic reliance on coinfection. However, whether IAV virus-virus interactions during coinfection with a heterologous strain are similarly beneficial had not been explored. To address this, we assessed the outcomes of heterologous virus-virus interactions by evaluating the extent to which a coinfecting IAV could augment the replication of a focal IAV. We found that virus-virus interactions within cells were largely beneficial, with IAVs having the lowest intrinsic reliance on coinfection most effectively augmenting replication of a focal IAV. However, competitive virus-virus interactions were dominant during multi-cycle infection. These findings suggest that coinfecting IAVs are significantly impacted by virus-virus interactions, with differing dominant virus-virus interactions between the within-cell and within-host scales. We have previously shown that the M segments of avian IAVs support aberrantly high M2 expression in mammalian cells. The M segment of the 2009 pandemic strain, although descended from that of an avian IAV, does not show this phenotype. However, the mechanism that re-establishes optimal M gene expression, was not well understood. Thus, we undertook to elucidate the mechanism underlying differential M segment gene regulation during avian and human IAV infection of a mammalian host. We found that avian IAV circulation in swine was associated with decreased M2 expression in mammalian cells. However, introducing M segment mutations that arose during IAV swine circulation into an avian precursor did not change M2 protein expression. Introducing regions of the 2009 H1N1 pandemic IAV did decrease avian M2 protein, but not mRNA, expression. These findings suggest that re-establishing regulation of M gene expression is necessary to overcome host restriction. Together, these studies further our understanding of the impacts of coinfection dynamics and host restriction on IAV replication in novel hosts.

Table of Contents

Chapter 1: Introduction…………………………………………………………………………1

           Introduction………………………………………………………………………………1

           Influenza viruses…………………………………………………………………………1

           IAV life cycle……………………………………………………………………………..2

           IAV evolution…………………………………………………………………………….5

           IAV hosts…………………………………………………………………………………6

           Overcoming species barriers…………………………………………………………….6

           Pandemic IAVs…………………………………………………………………………...7

           Virus-virus interactions……………………………………………………………….....8

           Dissertation aims…………………………………………………………………………9

           References……………………………………………………………………………….11

Chapter 2: Influenza A virus coinfection dynamics are shaped by distinct virus-virus interactions within and between cells………………………………………………………….2

           Abstract………………………………………………………………………………….24

           Introduction……………………………………………………………………………..25

           Results…………………………………………………………………………………...27

Discussion……………………………………………………………………………….39

Methods………………………………………………………………………………….44

Supplemental Information……………………………………………………………..51

References……………………………………………………………………………….57

Chapter 3: Regulation of gene expression from the influenza A virus M segment is a feature of host adaptation……………………………………………………………………...64

Abstract…………………………………………………………………………………64

           Introduction…………………………………………………………………………….65

           Results…………………………………………………………………………………...68

Discussion……………………………………………………………………………….76

Methods………………………………………………………………………………….79

Supplemental Information……………………………………………………………..84

References……………………………………………………………………………….86

Chapter 4: Discussion…………………………………………………………………………..92

           IAV virus-virus interactions…………………………………………………………...92

           M segment gene regulation…………………………………………………………….94

           Conclusion………………………………………………………………………………95

           References……………………………………………………………………………….97

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Microbiology & Molecular Genetics
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Virology Biology, Molecular Biology, Microbiology
Keyword	influenza virology coinfection virus-virus interactions
Committee Chair / Thesis Advisor	Lowen, Anice, Emory University
Committee Members	Conn, Graeme, Emory University Mainou, Bernardo, Centers for Disease Control and Prevention Melikian, Gregory, Emory University Steel, John, Centers for Disease Control and Prevention

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