NS1 mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections; insights into 1918 H1N1 pandemic?

[tetano]

J Infect Dis. 2014 Nov 2. pii: jiu609. [Epub ahead of print]
NS1 mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections; insights into 1918 H1N1 pandemic?
Hrincius ER1, Liedmann S2, Finkelstein D3, Vogel P4, Gansebom S1, Ehrhardt C2, Ludwig S2, Hains DS5, Webby R1, McCullers JA6.
Author information
Abstract

NS1 proteins from avian influenza viruses like the 1918 pandemic NS1 are capable of inhibiting the key signaling integrator c-Abl (Abl1), resulting in massive cytopathic cell alterations. In the current study, we addressed the consequences of NS1-mediated alteration of c-Abl on acute lung injury and pathogenicity. Comparing isogenic strains that differ only in their ability to inhibit c-Abl, we observed elevated pathogenicity for the c-Abl-inhibiting virus. NS1-mediated block of c-Abl resulted in severe lung pathology and massive edema formation and facilitated secondary bacterial pneumonia. This phenotype was independent of differences in replication and immune responses, defining it as an NS1 virulence mechanism distinct from its canonical functions. Microarray analysis revealed extensive downregulation of genes involved in cell integrity and vascular endothelial regulation. In conclusion, NS1 protein-mediated blockade of c-Abl signaling drives acute lung injury and primes for bacterial co-infections revealing potential insights into the pathogenicity of the 1918 pandemic virus.

? The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

PMID:
25367299
[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/25367299

 

[AlaskaDenise]

Re: NS1 mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections; insights into 1918 H1N1 pandemic?

The NS1 segment can contribute to multi-organ failure if F103L & M107I mutations are present.

This is discussed relevent to 1997 H5N1 here:

Influenza A/Hong Kong/156/1997(H5N1) virus NS1 gene mutations F103L and M106I both increase IFN antagonism, virulence and cytoplasmic localization but differ in binding to RIG-I and CPSF30.

Looking at the 2013 China H7N9 sequences, this mutation is also present in many cases. However, it is NOT present in the only 1918/H1N1 NS1 - Brevig Mission/1. One or the other shows up sporatically in H1N1 from the last few years.

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