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The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.

Kühn N, Bergmann S, Kösterke N, Lambertz RL, Keppner A, van den Brand JM, Pöhlmann S, Weiß S, Hummler E, Hatesuer B, Schughart K - J. Virol. (2016)

Bottom Line: In this study, we investigated an additional trypsin-like protease, TMPRSS4.Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality.Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.

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Levels of inflammatory cytokines and chemokines in BAL fluid samples from C57BL/6 and Tmprss2−/−Tmprss4−/− mice. Female C57BL/6J (black symbols) and Tmprss2−/−Tmprss4−/− (red symbols) mice were infected with 2 × 103 FFU of H3N2 influenza virus, and BAL fluid was collected on day 3 p.i. PBS-treated mice were used as mock controls (open symbols). Five biological replicates were analyzed at each time point. Individual values, means, and SEM are presented. Detection limits of the individual proteins are indicated by blue lines. Samples below the detection threshold were set to the respective detection limit. Significances were calculated using the Mann-Whitney U test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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Figure 5: Levels of inflammatory cytokines and chemokines in BAL fluid samples from C57BL/6 and Tmprss2−/−Tmprss4−/− mice. Female C57BL/6J (black symbols) and Tmprss2−/−Tmprss4−/− (red symbols) mice were infected with 2 × 103 FFU of H3N2 influenza virus, and BAL fluid was collected on day 3 p.i. PBS-treated mice were used as mock controls (open symbols). Five biological replicates were analyzed at each time point. Individual values, means, and SEM are presented. Detection limits of the individual proteins are indicated by blue lines. Samples below the detection threshold were set to the respective detection limit. Significances were calculated using the Mann-Whitney U test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: Furthermore, we measured the protein levels of inflammatory chemokines and cytokines in BAL fluid. Three days after infection, increases of the levels of 13 chemokines were observed in C57BL/6 mice compared to mock-infected mice. Most importantly, we observed significantly less expression of IP10, KC, MCP1, MIP1α, RANTES, VEGF, and TNF-α in knockout mice than in wild-type mice (Fig. 5). No detectable levels of IL-1α were observed in knockout samples at this time point.


The Proteolytic Activation of (H3N2) Influenza A Virus Hemagglutinin Is Facilitated by Different Type II Transmembrane Serine Proteases.

Kühn N, Bergmann S, Kösterke N, Lambertz RL, Keppner A, van den Brand JM, Pöhlmann S, Weiß S, Hummler E, Hatesuer B, Schughart K - J. Virol. (2016)

Levels of inflammatory cytokines and chemokines in BAL fluid samples from C57BL/6 and Tmprss2−/−Tmprss4−/− mice. Female C57BL/6J (black symbols) and Tmprss2−/−Tmprss4−/− (red symbols) mice were infected with 2 × 103 FFU of H3N2 influenza virus, and BAL fluid was collected on day 3 p.i. PBS-treated mice were used as mock controls (open symbols). Five biological replicates were analyzed at each time point. Individual values, means, and SEM are presented. Detection limits of the individual proteins are indicated by blue lines. Samples below the detection threshold were set to the respective detection limit. Significances were calculated using the Mann-Whitney U test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836353&req=5

Figure 5: Levels of inflammatory cytokines and chemokines in BAL fluid samples from C57BL/6 and Tmprss2−/−Tmprss4−/− mice. Female C57BL/6J (black symbols) and Tmprss2−/−Tmprss4−/− (red symbols) mice were infected with 2 × 103 FFU of H3N2 influenza virus, and BAL fluid was collected on day 3 p.i. PBS-treated mice were used as mock controls (open symbols). Five biological replicates were analyzed at each time point. Individual values, means, and SEM are presented. Detection limits of the individual proteins are indicated by blue lines. Samples below the detection threshold were set to the respective detection limit. Significances were calculated using the Mann-Whitney U test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: Furthermore, we measured the protein levels of inflammatory chemokines and cytokines in BAL fluid. Three days after infection, increases of the levels of 13 chemokines were observed in C57BL/6 mice compared to mock-infected mice. Most importantly, we observed significantly less expression of IP10, KC, MCP1, MIP1α, RANTES, VEGF, and TNF-α in knockout mice than in wild-type mice (Fig. 5). No detectable levels of IL-1α were observed in knockout samples at this time point.

Bottom Line: In this study, we investigated an additional trypsin-like protease, TMPRSS4.Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality.Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Infection Genetics, Helmholtz Centre for Infection Research, and University of Veterinary Medicine Hannover, Braunschweig, Germany.

Show MeSH
Related in: MedlinePlus