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.

Detection of Virus-Related Sequences Associated With Potential Etiologies of Hepatitis in Liver Tissue Samples From Rats, Mice, Shrews, and Bats

“…Although the sequences related to influenza A virus obtained from viral metagenomics showed a high degree of similarity with the neuraminidase gene and nucleocapsid protein gene sequences of influenza A virus, a relatively low similarity was found between the PCR-screened sequences and the matrix gene sequences of influenza A virus from GenBank. The matrix gene contributes to the host restriction of influenza A virus ( Calderon et al, 2019 ). It seems that the sequences related to influenza A virus in these animals might belong to two new viral species within the genus Alphainfluenzavirus , and these viruses may be host-specific.…”

Evolutionary pressures rendered by animal husbandry practices for avian influenza viruses to adapt to humans

“…If an avian IAV infects mammalian cells, excessive splicing of its M protein’s mRNA7 occurs and this causes viral interference in the mammalian host cells, blocking cellular processes that the virus would otherwise use to complete replication and budding. However, mutagenesis experiments of the M protein show that non-synonymous changes of amino acids in certain regions modulate the efficiency of mRNA7 splicing ( Calderon et al., 2019 ). It is reasonable, therefore, to speculate that avian CTLs from a population presenting few MHC class I alleles may select for mutants of the M protein that affect splicing of gene segment 7 that encodes for M protein in a way that renders it compatible with mammalian cellular processes.…”

Repurposing Chloroquine Against Multiple Diseases With Special Attention to SARS-CoV-2 and Associated Toxicity

“…Many of the human viruses employ autophagy for their replication inside the target cells (Table 2) (Yan et al, 2013;Calderon et al, 2019;Zhang et al, 2019). Though the role of autophagy in the proper functioning of SARS-CoV-2 is still under investigation, several results claim that autophagy is crucial for SARS-CoVs replication (Brest et al, 2020;Yang and Shen, 2020).…”