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

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.

SUBMITTER: Calderon BM

PROVIDER: S-EPMC6695095 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Calderon Brenda M BM Danzy Shamika S Delima Gabrielle K GK Jacobs Nathan T NT Ganti Ketaki K Hockman Megan R MR Conn Graeme L GL Lowen Anice C AC Steel John J

PLoS pathogens 20190815 8

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. ...[more]

PMID: 31415678

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Project description:The influenza A virus (IAV) genome is divided into eight negative-sense, single-stranded RNA segments. Each segment exhibits a unique level and temporal pattern of expression; however, the exact mechanisms underlying the patterns of individual gene segment expression are poorly understood. We previously demonstrated that a single substitution in the viral nucleoprotein (NP:F346S) selectively modulates neuraminidase (NA) gene segment expression while leaving other segments largely unaffected. Given what is currently known about NP function, there is no obvious explanation for how changes in NP can selectively modulate the replication of individual gene segments. In this study, we found that the specificity of this effect for the NA segment is virus strain specific and depends on the untranslated region (UTR) sequences of the NA segment. While the NP:F346S substitution did not significantly alter the RNA binding or oligomerization activities of NP in vitro, it specifically decreased the ability of NP to promote NA segment viral RNA (vRNA) synthesis. In addition to NP residue F346, we identified two other adjacent aromatic residues in NP (Y385 and F479) capable of similarly regulating NA gene segment expression, suggesting a larger role for this domain in gene-segment specific regulation. Our findings reveal a novel role for NP in selective regulation of viral gene segment replication and provide a framework for understanding how the expression patterns of individual viral gene segments can be modulated during adaptation to new host environments. IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen that remains a significant source of morbidity and mortality. Escape from host immunity or emergence into new host species often requires mutations that modulate the functional activities of the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA), which are responsible for virus attachment to and release from host cells, respectively. Maintaining the functional balance between the activities of HA and NA is required for fitness across multiple host systems. Thus, selective modulation of viral gene expression patterns may be a key determinant of viral immune escape and cross-species transmission potential. We identified a novel mechanism by which the viral nucleoprotein (NP) gene can selectively modulate NA segment replication and gene expression through interactions with the segment UTRs. Our work highlights an unexpected role for NP in selective regulation of expression from the individual IAV gene segments.

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

Publications

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

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