tetano
Editor, Senior Moderator
PLoS Pathog. 2019 Aug 15;15(8):e1007892. doi: 10.1371/journal.ppat.1007892. eCollection 2019 Aug.
[h=1]Dysregulation of M segment gene expression contributes to influenza A virus host restriction.[/h] Calderon BM[SUP]1[/SUP], Danzy S[SUP]1[/SUP], Delima GK[SUP]1[/SUP], Jacobs NT[SUP]1[/SUP], Ganti K[SUP]1[/SUP], Hockman MR[SUP]1[/SUP], Conn GL[SUP]2[/SUP], Lowen AC[SUP]1[/SUP], Steel J[SUP]1[/SUP].
[h=3]Author information[/h] 1 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States of America. 2 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, United States of America.
[h=3]Abstract[/h] 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.
PMID: 31415678 DOI: 10.1371/journal.ppat.1007892
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[h=1]Dysregulation of M segment gene expression contributes to influenza A virus host restriction.[/h] Calderon BM[SUP]1[/SUP], Danzy S[SUP]1[/SUP], Delima GK[SUP]1[/SUP], Jacobs NT[SUP]1[/SUP], Ganti K[SUP]1[/SUP], Hockman MR[SUP]1[/SUP], Conn GL[SUP]2[/SUP], Lowen AC[SUP]1[/SUP], Steel J[SUP]1[/SUP].
[h=3]Author information[/h] 1 Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States of America. 2 Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, United States of America.
[h=3]Abstract[/h] 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.
PMID: 31415678 DOI: 10.1371/journal.ppat.1007892
Free full text