Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 141, Issue 5, Pages 1799-1817Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2017.11.032
Keywords
Influenza A virus (IAV); CD151; nuclear export; host innate immunity; inflammasome; IAV severity
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Funding
- Singapore Ministry of Health's National Medical Research Council (NMRC) under its Individual Research Grant (IRG) scheme [NMRC/1215/2009]
- Academic Research Fund Tier 2 grant [MOE2015-T2-2]
- NMRC [NMRC/CIRG/1362/2013, NMRC/CIRG/1458/2016]
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Background: Despite advances in our understanding of the mechanisms of influenza A virus (IAV) infection, the crucial virus-host interactions during the viral replication cycle still remain incomplete. Tetraspanin CD151 is highly expressed in the human respiratory tract, but its pathological role in IAV infection is unknown. Objectives: We sought to characterize the functional role and mechanisms of action of CD151 in IAV infection of the upper and lower respiratory tracts with H1N1 and H3N2 strains. Methods: We used CD151-null mice in an in vivo model of IAV infection and clinical donor samples of in vitro-differentiated human nasal epithelial cells cultured at air-liquid interface. Results: As compared with wild-type infected mice, CD151-null infected mice exhibited a significant reduction in virus titer and improvement in survival that is associated with pronounced host antiviral response and inflammasome activation together with accelerated lung repair. Interestingly, we show that CD151 complexes newly synthesized viral proteins with host nuclear export proteins and stabilizes microtubule complexes, which are key processes necessary for the polarized trafficking of viral progeny to the host plasma membrane for assembly. Conclusions: Our results provide new mechanistic insights into our understanding of IAV infection. We show that CD151 is a critical novel host factor of nuclear export signaling whereby the IAV nuclear export uses it to complement its own nuclear export proteins (a site not targeted by current therapy), making this regulation unique, and holds promise for the development of novel alternative/complementary strategies to reduce IAV severity.
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