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Updated: Jan 20, 2026
Monitoring Influenza Virus Survival Outside the Host Using Real-Time Cell Analysis
Published on: February 20, 2021
Dysregulation of M segment gene expression contributes to influenza A virus host restriction
Brenda M Calderon1, Shamika Danzy1, Gabrielle K Delima1
1Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States of America.
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.
Insights
The M segment of influenza A virus (IAV) is key for host adaptation. Avian M segments restrict IAV growth and transmission in mammals by overexpressing M2, impacting cellular processes.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- The M segment of the 2009 pandemic influenza A virus (IAV) is crucial for its emergence in human populations.
- Understanding the genetic basis of IAV host adaptation is vital for pandemic preparedness.
Purpose of the Study:
- To investigate the genetic contributions of the M segment to IAV host adaptation.
- To elucidate the mechanisms by which the M segment influences viral growth and transmission.
Main Methods:
- Examined isogenic viruses with avian- or human-derived M segments in mammalian models.
- Analyzed M1 and M2 protein expression levels and their correlation with viral replication.
- Investigated the role of M2 protein in autophagosome accumulation and vesicular homeostasis.
- Differentiated synonymous and non-synonymous changes within the M segment.
Main Results:
- Avian M segments restricted viral growth and transmission in mammals, correlating with higher M2 relative to M1 expression.
- M2 overexpression led to autophagosome accumulation, which was mitigated by amantadine.
- Replication was diminished by M2 overexpression, irrespective of M1/M2 amino acid sequences.
- Human M segment viruses expressing low levels of avian M2 showed inefficient transmission despite efficient replication.
Conclusions:
- The IAV M2 protein contains determinants essential for viral transmission.
- Regulation of M segment gene expression is critical for IAV host adaptation, preventing M2-induced disruption of vesicular homeostasis.
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