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

• Type of Material: Article
• Authors: Brenda M. Calderon, Emory University; Shamika Danzy, Emory University; Gabrielle K. Delima, Emory University; Nathan T. Jacobs, Emory University; Ketaki Ganti, Emory University; Megan R. Hockman, Emory University; Graeme L Conn, Emory University; Anice Carmen Lowen, Emory University; John Steel, Emory University
• Language: English
• Date: 2019-08-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Calderon et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1007892
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 15
• Issue: 8
• Start Page: e1007892
• End Page: e1007892
• Grant/Funding Information: This work was funded by the National Institute of Allergy and Infectious Disease through the Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract no. HHSN272201400004C.
• Keywords: Microbiology; NUCLEAR EXPORT; AMINO-ACID; DENGUE VIRUS; Science & Technology; ION-CHANNEL; MATRIX PROTEIN-2; AUTOPHAGY; RNA SEGMENT-7; Virology; Life Sciences & Biomedicine; ABORTIVE INFECTION; SELECTIVE PERTURBATION; Parasitology; GUINEA-PIG
• Research Categories: Biology, Virology; Chemistry, Biochemistry

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.