Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice

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Annual influenza epidemics and occasional pandemics pose a severe threat to human health. Host cell factors required for viral spread but not for cellular survival are attractive targets for novel approaches to antiviral intervention. The cleavage activation of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity. However, it is unknown which proteases activate influenza viruses in mammals. Several candidates have been identified in cell culture studies, leading to the concept that influenza viruses can employ multiple enzymes to ensure their cleavage activation in the host. Here, we show that deletion of a single HA-activating protease gene, Tmprss2, in mice inhibits spread of mono-basic H1N1 influenza viruses, including the pandemic 2009 swine influenza virus. Lung pathology was strongly reduced and mutant mice were protected from weight loss, death and impairment of lung function. Also, after infection with mono-basic H3N2 influenza A virus body weight loss and survival was less severe in Tmprss2 mutant compared to wild type mice. As expected, Tmprss2-deficient mice were not protected from viral spread and pathology after infection with multi-basic H7N7 influenza A virus. In conclusion, these results identify TMPRSS2 as a host cell factor essential for viral spread and pathogenesis of mono-basic H1N1 and H3N2 influenza A viruses.

Vyšlo v časopise: Tmprss2 Is Essential for Influenza H1N1 Virus Pathogenesis in Mice. PLoS Pathog 9(12): e32767. doi:10.1371/journal.ppat.1003774
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003774

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Zdroje

1. HurtAC, ChotpitayasunondhT, CoxNJ, DanielsR, FryAM, et al. (2012) Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis 12 : 240–248.

2. KlenkHD, RottR, OrlichM, BlodornJ (1975) Activation of influenza A viruses by trypsin treatment. Virology 68 : 426–439.

3. LazarowitzSG, ChoppinPW (1975) Enhancement of the infectivity of influenza A and B viruses by proteolytic cleavage of the hemagglutinin polypeptide. Virology 68 : 440–454.

4. Stieneke-GroberA, VeyM, AnglikerH, ShawE, ThomasG, et al. (1992) Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. EMBO J 11 : 2407–2414.

5. KidoH, YokogoshiY, SakaiK, TashiroM, KishinoY, et al. (1992) Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. A possible activator of the viral fusion glycoprotein. J Biol Chem 267 : 13573–13579.

6. MurakamiM, TowatariT, OhuchiM, ShiotaM, AkaoM, et al. (2001) Mini-plasmin found in the epithelial cells of bronchioles triggers infection by broad-spectrum influenza A viruses and Sendai virus. Eur J Biochem 268 : 2847–2855.

7. BertramS, GlowackaI, SteffenI, KuhlA, PohlmannS (2010) Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol 20 : 298–310.

8. ZhirnovOP, IkizlerMR, WrightPF (2002) Cleavage of influenza a virus hemagglutinin in human respiratory epithelium is cell associated and sensitive to exogenous antiproteases. J Virol 76 : 8682–8689.

9. Böttcher-FriebertshauserE, SteinDA, KlenkHD, GartenW (2011) Inhibition of influenza virus infection in human airway cell cultures by an antisense peptide-conjugated morpholino oligomer targeting the hemagglutinin-activating protease TMPRSS2. J Virol 85 : 1554–1562.

10. BertramS, GlowackaI, BlazejewskaP, SoilleuxE, AllenP, et al. (2010) TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells. J Virol 84 : 10016–10025.

11. BöttcherE, MatrosovichT, BeyerleM, KlenkHD, GartenW, et al. (2006) Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80 : 9896–9898.

12. WangW, XieH, YeZ, VassellR, WeissCD (2010) Characterization of lentiviral pseudotypes with influenza H5N1 hemagglutinin and their performance in neutralization assays. J Virol Methods 165 : 305–310.

13. BertramS, HeurichA, LavenderH, GiererS, DanischS, et al. (2012) Influenza and SARS-Coronavirus Activating Proteases TMPRSS2 and HAT Are Expressed at Multiple Sites in Human Respiratory and Gastrointestinal Tracts. PLoS ONE 7: e35876.

14. KimTS, HeinleinC, HackmanRC, NelsonPS (2006) Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol 26 : 965–975.

15. BlazejewskaP, KoscinskiL, ViegasN, AnhlanD, LudwigS, et al. (2011) Pathogenicity of different PR8 influenza A virus variants in mice is determined by both viral and host factors. Virology 412 : 36–45.

16. HallerO, ArnheiterH, LindenmannJ (1979) Natural, genetically determined resistance toward influenza virus in hemopoietic mouse chimeras. Role of mononuclear phagocytes. J Exp Med 150 : 117–126.

17. ChaipanC, KobasaD, BertramS, GlowackaI, SteffenI, et al. (2009) Proteolytic activation of the 1918 influenza virus hemagglutinin. J Virol 83 : 3200–3211.

18. KidoH, OkumuraY, YamadaH, LeTQ, YanoM (2007) Proteases essential for human influenza virus entry into cells and their inhibitors as potential therapeutic agents. Curr Pharm Des 13 : 405–414.

19. GotohB, OgasawaraT, ToyodaT, InocencioNM, HamaguchiM, et al. (1990) An endoprotease homologous to the blood clotting factor X as a determinant of viral tropism in chick embryo. EMBO J 9 : 4189–4195.

20. GotohB, YamauchiF, OgasawaraT, NagaiY (1992) Isolation of factor Xa from chick embryo as the amniotic endoprotease responsible for paramyxovirus activation. FEBS Lett 296 : 274–278.

21. GallowaySE, ReedML, RussellCJ, SteinhauerDA (2013) Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: Implications for host range and adaptation. PLoS Pathog 9: e1003151.

22. HamiltonBS, GludishDW, WhittakerGR (2012) Cleavage Activation of the Human-Adapted Influenza Virus Subtypes by Matriptase Reveals Both Subtype -⁠ and Strain-Specificity. J Virol 86 : 10579–86.

23. HamiltonBS, WhittakerGR (2013) Cleavage activation of human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12. J Biol Chem 288 : 17399–17407.

24. ZhirnovOP, KlenkHD, WrightPF (2011) Aprotinin and similar protease inhibitors as drugs against influenza. Antiviral Res 92 : 27–36.

25. BahgatMM, BlazejewskaP, SchughartK (2011) Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection. Virol J 8 : 27.

26. ZhirnovOP, OvcharenkoAV, BukrinskayaAG (1984) Suppression of influenza virus replication in infected mice by protease inhibitors. J Gen Virol 65 (Pt 1): 191–196.

27. ZhirnovOP (1987) High protection of animals lethally infected with influenza virus by aprotinin-rimantadine combination. J Med Virol 21 : 161–167.

28. OvcharenkoAV, ZhirnovOP (1994) Aprotinin aerosol treatment of influenza and paramyxovirus bronchopneumonia of mice. Antiviral Res 23 : 107–118.

29. ShiroganeY, TakedaM, IwasakiM, IshiguroN, TakeuchiH, et al. (2008) Efficient multiplication of human metapneumovirus in Vero cells expressing the transmembrane serine protease TMPRSS2. J Virol 82 : 8942–8946.

30. GiererS, BertramS, KaupF, WrenschF, HeurichA, et al. (2013) The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol 87 : 5502–5511.

31. ShiratoK, KawaseM, MatsuyamaS (2013) Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Infection Mediated by the Transmembrane Serine Protease TMPRSS2. J Virol doi: 10.1128/JVI.01890-13

32. GlowackaI, BertramS, MullerMA, AllenP, SoilleuxE, et al. (2011) Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol 85 : 4122–4134.

33. ShullaA, Heald-SargentT, SubramanyaG, ZhaoJ, PerlmanS, et al. (2011) A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol 85 : 873–882.

34. MatsuyamaS, NagataN, ShiratoK, KawaseM, TakedaM, et al. (2010) Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol 84 : 12658–12664.

35. GabrielG, DauberB, WolffT, PlanzO, KlenkHD, et al. (2005) The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A 102 : 18590–18595.

36. HoffmannE, StechJ, LenevaI, KraussS, ScholtissekC, et al. (2000) Characterization of the Influenza a Virus Gene Pool in Avian Species in Southern China: Was H6N1 a Derivative or a Precursor of H5N1? Journal of Virology 74 : 6309–6315.

37. WilkE, SchughartK (2012) The mouse as model system to study host-pathogen interactions in influenza A infections. Curr Protoc Mouse Biol 2 : 177–205.

38. GrimmD, StaeheliP, HufbauerM, KoernerI, Martínez-SobridoL, et al. (2007) Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene. PNAS 104 : 6806–6811.

39. GerlachT, KuhlingL, UhlendorffJ, LaukemperV, MatrosovichT, et al. (2012) Characterization of the neuraminidase of the H1N1/09 pandemic influenza virus. Vaccine 30 : 7348–52.