Dysregulation of M segment gene expression contributes to influenza A virus host restriction.

Brenda M Calderon,Nathan T Jacobs,Gabrielle K Delima,Graeme L Conn,Shamika Danzy,Megan R Hockman,Ketaki Ganti,John Steel,Anice C Lowen,Stacey Schultz-Cherry

doi:10.1371/journal.ppat.1007892

Abstract

The M segment of the 2009 pandemic influenza A virus (IAV) has been implicated in its emergence into human populations. To elucidate the genetic contributions of the M segment to host adaptation, and the underlying mechanisms, we examined a panel of isogenic viruses that carry avian- or human-derived M segments. Avian, but not human, M segments restricted viral growth and transmission in mammalian model systems, and the restricted growth correlated with increased expression of M2 relative to M1. M2 overexpression was associated with intracellular accumulation of autophagosomes, which was alleviated by interference of the viral proton channel activity by amantadine treatment. As M1 and M2 are expressed from the M mRNA through alternative splicing, we separated synonymous and non-synonymous changes that differentiate human and avian M segments and found that dysregulation of gene expression leading to M2 overexpression diminished replication, irrespective of amino acid composition of M1 or M2. Moreover, in spite of efficient replication, virus possessing a human M segment that expressed avian M2 protein at low level did not transmit efficiently. We conclude that (i) determinants of transmission reside in the IAV M2 protein, and that (ii) control of M segment gene expression is a critical aspect of IAV host adaptation needed to prevent M2-mediated dysregulation of vesicular homeostasis.

Highlights

Influenza A virus (IAV) epidemics and pandemics result in widespread and often severe disease [1,2,3], as well as considerable societal economic costs [4]
Influenza A virus (IAV) pandemics arise when a virus adapted to a non-human host overcomes species barriers to successfully infect humans and sustain human-to-human transmission
To gauge the adaptive potential and pandemic risk posed by a particular IAV, it is critical to understand the mechanisms underlying viral adaptation to human hosts

Summary

Introduction

Influenza A virus (IAV) epidemics and pandemics result in widespread and often severe disease [1,2,3], as well as considerable societal economic costs [4]. Sporadic transmission of IAV from avian reservoirs to humans occurs mainly through domesticated intermediate hosts such as chickens and pigs [5]. Infection of humans with H7N9 and H5N1 subtype IAVs occurs through direct exposure to infected poultry. They often cause severe disease, these zoonotic cases have not led to sustained onward transmission to date and have not caused a pandemic. Despite abundant circulation of IAVs at the animalhuman interface, pandemics occur only rarely owing to the host specificity of IAV infection. With the goal of anticipating and mitigating IAV emergence in humans, it is essential to understand the species-specific barriers to infection and the mechanisms by which IAV evolution allows these impediments to be overcome

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Conclusion