Reassortment Potential and Coinfection Dependence of Influenza A Virus is Determined through Collective Virus-Virus and Virus-Host Interactions Restricted; Files Only

Phipps, Kara (Fall 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/0v838165c?locale=es
Published

Abstract

Influenza A virus (IAV) poses a significant threat to public health due to its constant evolution. IAVs diversify through the mutations produced by the error prone viral polymerase and gene reassortment, which occurs when two viruses co-infect the same cell and exchange gene segments. Collective interactions among coinfecting IAVs have been observed to increase genotypic diversity and productivity. However, the factors which constrain or enhance collective IAV interactions and genetic diversity potential are incompletely characterized. Segment mismatch refers to incompatibilities among gene segments and is predicted to constrain genetic diversity arising from heterologous IAV coinfections. To better understand how segment mismatch may constrain genetic exchange, this study evaluates the potential for reassortment of heterologous, representative strains of pandemic H1N1 (pH1N1) and seasonal H3N2 lineages. Results of heterologous co-infections were compared to those obtained from co-infection with homologous, genetically tagged, pH1N1 viruses. Reassortment was abundant for both, but biases for particular gene pairings were observed with heterologous IAVs. The impact of these preferences was investigated by measuring correlates of replication and viral fitness. Transmission of pH1N1/H3N2 reassortant genotypes between guinea pigs was detected, but parental H3N2 viruses dominated in vivo. Segment mismatch among pH1N1 and H3N2 viruses likely impact potential reassortment outcomes to constrain IAV diversification. The second study further investigates the factors which impact collective interactions among IAVs. Reassortment frequency was quantified for a panel of IAVs in multiple cell lines and relevant animal models. Dependence on IAV coinfection was found to vary with virus strain and host. The abundance of incomplete viral genomes only partially explained coinfection dependence. Rather, additional RNA quantification and viral productivity measurements revealed that viral replication is augmented by collective virus-virus interactions in a cooperative, host dependent manner. The viral polymerase was identified as the major determinant of the observed degree of reliance on coinfection. These studies together highlight the prevalence and importance of virus-virus and virus-host interactions in determining the potential for viral diversification through IAV coinfection. This work furthers our understanding of the constraints acting on IAV genetic diversification and establishes newfound importance for collective interactions in the IAV life cycle.

Table of Contents

Abstract

Acknowledgments

Table of Contents

List of Figures and Tables

Author Contributions

Chapter I. Introduction……………………………………………………………………....…1

Introduction ....................................................................................................................................1

References......................................................................................................................................18

Chapter II. Seasonal H3N2 and 2009 pandemic H1N1 influenza A viruses reassort efficiently but produce attenuated progeny....29

Abstract ..........................................................................................................................................30

Introduction ....................................................................................................................................31

Results.............................................................................................................................................34

Discussion.......................................................................................................................................46

Materials and Methods....................................................................................................................50

Acknowledgements….....................................................................................................................57

Figures and Tables…......................................................................................................................58

References.......................................................................................................................................74

Supplemental Information...............................................................................................................81

Chapter III. Collective interactions augment influenza A virus replication in a host-dependent manner…84

Abstract ..........................................................................................................................................85

Introduction ....................................................................................................................................86

Results.............................................................................................................................................89

Discussion.......................................................................................................................................100

Materials and Methods....................................................................................................................105

Acknowledgements….....................................................................................................................118

Figures and Tables….......................................................................................................................119

References.......................................................................................................................................130

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