An #NS1 #protein #mutation (I64T) affects #interferon responses and #virulence of circulating #H3N2 human #influenza A viruses (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

An NS1 protein mutation (I64T) affects interferon responses and virulence of circulating H3N2 human influenza A viruses

Marta L. DeDiego1,2, Aitor Nogales2, Kris Lambert-Emo1,2, Luis Martinez-Sobrido2 and David J. Topham1,2*

Author Affiliations: 1David Smith Center for Immunology and Vaccine Biology, and 2Department of Microbiology and Immunology, University of Rochester, Rochester, New York, USA.

 

ABSTRACT

Influenza NS1 protein is the main viral protein counteracting host innate immune responses, allowing the virus to efficiently replicate in interferon (IFN)-competent systems. In this manuscript, we analyzed NS1 protein variability within influenza A (IAV) H3N2 viruses infecting humans during the 2012/2013 season. We also evaluated the impact of the mutations on the ability of NS1 proteins to inhibit the host innate immune responses and general gene expression. Surprisingly, a previously unidentified mutation in the double stranded (ds)RNA-binding domain (I64T) decreased NS1-mediated general inhibition of host protein synthesis, by decreasing its interaction with the cleavage and polyadenylation specificity factor 30 (CPSF30), leading to increased innate immune responses after viral infection. Notably, a recombinant A/Puerto Rico/8/34 H1N1 virus encoding the H3N2 NS1-T64 protein was highly attenuated in mice, most likely because of its ability to induce higher antiviral IFN responses at early times after infection, and because this virus is highly sensitive to the IFN-induced antiviral state. Interestingly, using Peripheral Blood Mononuclear Cells (PBMCs) collected at the acute visit (days 2-3 after infection), we show that the subject infected with the NS1-T64 attenuated virus has diminished responses to interferon and to interferon induction, suggesting why this subject could be infected with this highly IFN-sensitive virus. These data demonstrate the importance of influenza virus surveillance to identify new mutations in the NS1 protein affecting its ability to inhibit innate immune responses, and as a consequence, the pathogenicity of the virus.

 

Importance

Influenza A and B viruses are one of the most common causes of respiratory infections in humans, causing 1 billion infections, and between 300,000 and 500,000 deaths annually. Influenza virus surveillance to identify new mutations in the NS1 protein affecting innate immune responses, and as a consequence, the pathogenicity of the circulating viruses is highly relevant. Here, we analyzed amino acid variability in the NS1 proteins from human seasonal viruses, and the effect of the mutations in innate immune responses and virus pathogenesis. A previously unidentified mutation in the dsRNA-binding domain decreased NS1-mediated general inhibition of host protein synthesis and the interaction of the protein with CPSF30. This mutation led to increased innate immune responses after viral infection, augmented IFN-sensitivity and virus attenuation in mice. Interestingly, using PBMCs, the subject infected with the virus encoding the attenuating mutation induced decreased antiviral responses, suggesting why this subject could be infected with this virus.

 

FOOTNOTES

*Corresponding author. David Smith Center for Immunology and Vaccine Biology, and Department of Microbiology and Immunology University of Rochester Medical Center. 601 Elmwood ave, box 609. Rochester, NY 14642., E-mail: David_Topham@URMC.rochester.edu

Copyright © 2016 DeDiego et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Research; Abstracts; Seasonal Influenza; H3N2.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.