Role of the M Segment in Influenza A Virus Transmission Open Access

Campbell, Patricia (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/s1784m691?locale=en
Published

Abstract

Influenza pandemics are caused by the emergence of antigenically distinct and highly transmissible influenza viruses within human populations. These viruses result from reassortment within an animal reservoir and likely adapt to productively transmit between humans. Recent studies suggested that the M segment contributes to the transmissibility of the 2009 pandemic H1N1 influenza virus [pH1N1], although the underlying mechanism(s) remain unknown. In addition, a balance between hemagglutinin (HA) receptor binding and neuraminidase (NA) receptor destroying activities was found to be important for pH1N1 transmission. The M segment encodes the matrix protein (M1) and the proton channel (M2). M1 is a major determinant of virus morphology and interacts with the NA and HA glycoproteins. We hypothesized that the M segment could impact virus transmission by altering virus morphology and NA/HA balance. Using the guinea pig model, we demonstrated that introduction of the pH1N1 A/Netherlands/602/2009 (H1N1) [NL602] M segment into an otherwise non-transmissible A/Puerto Rico/8/34 (H1N1) [PR8] background significantly increased virus contact transmission, and when combined with its cognate HA+NA, recapitulated the high transmission efficiency of the wild-type pH1N1 strain. Evaluation of the morphology and NA activity of these reassortant viruses revealed a correlation between filamentous morphology, as well as NA activity, and transmission. In addition, a naturally-occurring M1 polymorphism (A41P), in the Eurasian avian-like swine [EAsw] strain, A/swine/Spain/53207/2004 (H1N1) [SPN04], impacted replication and transmission of wild type SPN04- and PR8-based reassortant viruses, although no clear correlation with morphology or NA activity was established. Lastly, since the pH1N1 M segment originated within the EAsw lineage, and EAsw viruses do not readily transmit between humans, we hypothesized that pH1N1 M segment residues not present in the EAsw M segment would impact virus transmission. We demonstrated that PR8-based viruses harboring an EAsw M segment, or the NL602 M segment containing an EAsw M1 protein, did not replicate or transmit as well as the PR8/NL602 M virus, and transmission correlated with a filamentous morphology. Furthermore, all three residues that differed between the pH1N1 and EAsw M1 proteins individually decreased transmission of the PR8/NL602 M virus, although only one (N207S) was significant. Taken together, these results demonstrate that residues within the matrix protein can impact transmission of influenza A viruses and may concurrently alter virus morphology and NA activity, although neither is sufficient nor necessary for transmission.

Table of Contents

TABLE OF CONTENTS

Abstract

Acknowledgements

Table of Contents

List of Figures and Tables

Introduction

Influenza Virus Classification and Host Range

Influenza A Virus Life Cycle

Influenza A Virus Matrix Protein

Influenza A Virus: Human Disease and Pandemics

History of North American and European Swine Influenza

Influenza A Virus Structure and Morphology

Influenza A Virus Transmission and Host Adaptation

Chapter 1: The M Segment of the 2009 Pandemic Influenza Virus Confers Increased Neuraminidase Activity, Filamentous Morphology, and Efficient Contact Transmissibility to A/Puerto Rico/8/1934-Based Reassortant Viruses

Abstract

Importance

Introduction

Materials and Methods

Results

Discussion

References

Chapter 2: Residue 41 of the Eurasian avian-like swine influenza A virus matrix protein modulates virion filament length and efficiency of contact transmission

Abstract

Importance

Introduction

Materials and Methods

Results

Discussion

References

Chapter 3: Reassortant viruses harboring the 2009 pandemic influenza virus matrix protein have replication and transmission advantages over those containing a matrix protein from the pandemic precursor Eurasian avian-like swine lineage

Abstract

Introduction

Materials and Methods

Results

Discussion

References

Chapter 4: Conclusion

Collective introduction of pH1N1 M, NA, and HA segments into an otherwise non- transmissible virus reproduces the 100% transmission efficiency of wild-type pH1N1 in the guinea pig model

A single amino acid change within the IAV matrix protein can simultaneously alter virus morphology, NA activity, and transmission efficiency in the guinea pig model

The pH1N1 M segment confers transmissibility to an otherwise non- transmissible recombinant virus through functions encoded by its matrix protein

Novel swine H3N2v viruses contain the pH1N1 M segment, transmit more readily to humans than other swine-origin IAVs, and can cause limited human-to- human transmission

Overall Conclusions

References

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