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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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Tmprss4−/− mice are not resistant to H1N1 and H3N2 virus infection. Eight- to 11-week-old female mice were infected with 2 × 105 FFU of mouse-adapted PR8M virus (A/PuertoRico/8/34) (A), 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (B), or 10 FFU of H3N2 influenza virus (C) by intranasal application. Body weight loss was monitored until day 14 p.i. Mice with a weight loss of >30% of the starting body weight were euthanized and recorded as dead. Weight loss data represent mean values ± standard errors of the means (SEM). No significant differences in body weight loss and survival were observed between knockout and wild-type mice. Significances were calculated using the Mann-Whitney U test (body weight loss) and the log rank test (survival).
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Figure 2: Tmprss4−/− mice are not resistant to H1N1 and H3N2 virus infection. Eight- to 11-week-old female mice were infected with 2 × 105 FFU of mouse-adapted PR8M virus (A/PuertoRico/8/34) (A), 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (B), or 10 FFU of H3N2 influenza virus (C) by intranasal application. Body weight loss was monitored until day 14 p.i. Mice with a weight loss of >30% of the starting body weight were euthanized and recorded as dead. Weight loss data represent mean values ± standard errors of the means (SEM). No significant differences in body weight loss and survival were observed between knockout and wild-type mice. Significances were calculated using the Mann-Whitney U test (body weight loss) and the log rank test (survival).

Mentions: Wild-type as well as Tmprss4−/− mice were infected with mouse-adapted PR8M virus (A/PuertoRico/8/34; H1N1). Both wild-type and Tmprss4−/− mice lost weight after infection, with comparable kinetics, and showed similar survival rates (Fig. 2A). Analogous results were obtained after infection with two additional H1N1 virus variants (PR8F and A/WSN/33) (data not shown) and after infection with a multibasic, mouse-adapted H7N7 virus (A/Seal/Massachusetts/1/80) (data not shown). After infection with 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (17), body weight loss and survival were not different between the two mouse strains (Fig. 2B). Also, no statistically significant difference was observed after infection with a lower dose (10 FFU) of H3N2 virus (Fig. 2C). Measurement of viral loads in lungs of infected mice revealed equal viral loads in wild-type and Tmprss4 knockout mice at days 2, 3, and 4 p.i. (Fig. 3). These results indicated that loss of Tmprss4 in knockout mice does not protect mice from virus replication, spreading, or pathogenesis after infection with H3N2 or H1N1 influenza virus in comparison to wild-type mice.


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)

Tmprss4−/− mice are not resistant to H1N1 and H3N2 virus infection. Eight- to 11-week-old female mice were infected with 2 × 105 FFU of mouse-adapted PR8M virus (A/PuertoRico/8/34) (A), 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (B), or 10 FFU of H3N2 influenza virus (C) by intranasal application. Body weight loss was monitored until day 14 p.i. Mice with a weight loss of >30% of the starting body weight were euthanized and recorded as dead. Weight loss data represent mean values ± standard errors of the means (SEM). No significant differences in body weight loss and survival were observed between knockout and wild-type mice. Significances were calculated using the Mann-Whitney U test (body weight loss) and the log rank test (survival).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 2: Tmprss4−/− mice are not resistant to H1N1 and H3N2 virus infection. Eight- to 11-week-old female mice were infected with 2 × 105 FFU of mouse-adapted PR8M virus (A/PuertoRico/8/34) (A), 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (B), or 10 FFU of H3N2 influenza virus (C) by intranasal application. Body weight loss was monitored until day 14 p.i. Mice with a weight loss of >30% of the starting body weight were euthanized and recorded as dead. Weight loss data represent mean values ± standard errors of the means (SEM). No significant differences in body weight loss and survival were observed between knockout and wild-type mice. Significances were calculated using the Mann-Whitney U test (body weight loss) and the log rank test (survival).
Mentions: Wild-type as well as Tmprss4−/− mice were infected with mouse-adapted PR8M virus (A/PuertoRico/8/34; H1N1). Both wild-type and Tmprss4−/− mice lost weight after infection, with comparable kinetics, and showed similar survival rates (Fig. 2A). Analogous results were obtained after infection with two additional H1N1 virus variants (PR8F and A/WSN/33) (data not shown) and after infection with a multibasic, mouse-adapted H7N7 virus (A/Seal/Massachusetts/1/80) (data not shown). After infection with 2 × 103 FFU of mouse-adapted H3N2 virus (A/HongKong/01/68) (17), body weight loss and survival were not different between the two mouse strains (Fig. 2B). Also, no statistically significant difference was observed after infection with a lower dose (10 FFU) of H3N2 virus (Fig. 2C). Measurement of viral loads in lungs of infected mice revealed equal viral loads in wild-type and Tmprss4 knockout mice at days 2, 3, and 4 p.i. (Fig. 3). These results indicated that loss of Tmprss4 in knockout mice does not protect mice from virus replication, spreading, or pathogenesis after infection with H3N2 or H1N1 influenza virus in comparison to wild-type mice.

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