A Novel Role for PDZ-Binding Motif of Influenza A Virus Nonstructural Protein 1 in Regulation of Host Susceptibility to Postinfluenza Bacterial Superinfections

Authors

Kelly M. Shepardson, Kyle Larson, Hanbyul Cho, Laura L. Johns, Zeynep Malkoc, Kayla Stanek, Julia Wellhman, Sarah Zaiser, Jaelyn Daggs-Olson, Travis Moodie, Joshua M. Klonoski, Victor C. Huber, Agnieszka Rynda-Apple

Publication

Viral Immunology

Abstract

Influenza A viruses (IAVs) have multiple mechanisms for altering the host immune response to aid in virus survival and propagation. While both type I and II interferons (IFNs) have been associated with increased bacterial superinfection (BSI) susceptibility, we found that in some cases type I IFNs can be beneficial for BSI outcome. Specifically, we have shown that antagonism of the type I IFN response during infection by some IAVs can lead to the development of deadly BSI. The nonstructural protein 1 (NS1) from IAV is well known for manipulating host type I IFN responses, but the viral proteins mediating BSI severity remain unknown. In this study, we demonstrate that the PDZ-binding motif (PDZ-bm) of the NS1 C-terminal region from mouse-adapted A/Puerto Rico/8/34-H1N1 (PR8) IAV dictates BSI susceptibility through regulation of IFN-alpha/beta production. Deletion of the NS1 PDZ-bm from PR8 IAV (PR8-TRUNC) resulted in 100% survival and decreased bacterial burden in superinfected mice compared with 0% survival in mice superinfected after PR8 infection. This reduction in BSI susceptibility after infection with PR8-TRUNC was due to the presence of IFN-beta, as protection from BSI was lost in Ifn-beta-/- mice, resembling BSI during PR8 infection. PDZ-bm in PR8-infected mice inhibited the production of IFN-beta posttranscriptionally, and both delayed and reduced expression of the tunable interferon-stimulated genes. Finally, a similar lack of BSI susceptibility, due to the presence of IFN-beta on day 7 post-IAV infection, was also observed after infection of mice with A/TX98-H3N2 virus that naturally lacks a PDZ-bm in NS1, indicating that this mechanism of BSI regulation by NS1 PDZ-bm may not be restricted to PR8 IAV. These results demonstrate that the NS1 C-terminal PDZ-bm, like the one present in PR8 IAV, is involved in controlling susceptibility to BSI through the regulation of IFN-beta, providing new mechanisms for NS1-mediated manipulation of host immunity and BSI severity.

Links

 

How is this information collected?

This collection of Montana State authored publications is collected by the Library to highlight the achievements of Montana State researchers and more fully understand the research output of the University. They use a number of resources to pull together as complete a list as possible and understand that there may be publications that are missed. If you note the omission of a current publication or want to know more about the collection and display of this information email Leila Sterman.