Modulation of Influenza A virus NS1 expression reveals prioritization of host response antagonism at single-cell resolution.

Autor:	Yang Q; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States., Elz AE; Innovation Laboratory, Fred Hutchinson Cancer Center, Seattle, WA, United States., Panis M; Department of Microbiology, New York University, New York, NY, United States., Liu T; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States., Nilsson-Payant BE; TWINCORE Centre for Experimental and Clinical Infection Research, Institute of Experimental Virology, Hannover, Germany.; Cluster of Excellence RESIST (EXC 2155), Hanover Medical School, Hanover, Germany., Blanco-Melo D; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.; Herbold Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in microbiology [Front Microbiol] 2023 Oct 09; Vol. 14, pp. 1267078. Date of Electronic Publication: 2023 Oct 09 (Print Publication: 2023).
DOI:	10.3389/fmicb.2023.1267078
Abstrakt:	Influenza A virus (IAV) is an important human respiratory pathogen that causes significant seasonal epidemics and potential devastating pandemics. As part of its life cycle, IAV encodes the multifunctional protein NS1, that, among many roles, prevents immune detection and limits interferon (IFN) production. As distinct host immune pathways exert different selective pressures against IAV, as replication progresses, we expect a prioritization in the host immune antagonism by NS1. In this work, we profiled bulk transcriptomic differences in a primary bronchial epithelial cell model facing IAV infections at distinct NS1 levels. We further demonstrated that, at single cell level, the intracellular amount of NS1 in-part shapes the heterogeneity of the host response. We found that modulation of NS1 levels reveal a ranking in its inhibitory roles: modest NS1 expression is sufficient to inhibit immune detection, and thus the expression of pro-inflammatory cytokines (including IFNs), but higher levels are required to inhibit IFN signaling and ISG expression. Lastly, inhibition of chaperones related to the unfolded protein response requires the highest amount of NS1, often associated with later stages of viral replication. This work demystifies some of the multiple functions ascribed to IAV NS1, highlighting the prioritization of NS1 in antagonizing the different pathways involved in the host response to IAV infection. Competing Interests: QY is a co-founder of, equity holder of, and consultant for Darwin Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Yang, Elz, Panis, Liu, Nilsson-Payant and Blanco-Melo.)
Databáze:	MEDLINE
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