1887

Abstract

Hantaviruses are emerging zoonotic pathogens that can cause severe disease in humans. Clinical observations suggest that human immune components contribute to hantavirus-induced pathology. To address this issue we generated mice with a humanized immune system. Hantavirus infection of these animals resulted in systemic infection associated with weight loss, decreased activity, ruffled fur and inflammatory infiltrates of lung tissue. Intriguingly, after infection, humanized mice harbouring human leukocyte antigen (HLA) class I-restricted human CD8+ T cells started to lose weight earlier (day 10) than HLA class I-negative humanized mice (day 15). Moreover, in these mice the number of human platelets dropped by 77 % whereas the number of murine platelets did not change, illustrating how differences between rodent and human haemato-lymphoid systems may contribute to disease development. To our knowledge this is the first description of a humanized mouse model of hantavirus infection, and our results indicate a role for human immune cells in hantaviral pathogenesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.000087
2015-06-01
2019-12-06
Loading full text...

Full text loading...

/deliver/fulltext/jgv/96/6/1258.html?itemId=/content/journal/jgv/10.1099/vir.0.000087&mimeType=html&fmt=ahah

References

  1. Billerbeck E., Horwitz J. A., Labitt R. N., Donovan B. M., Vega K., Budell W. C., Koo G. C., Rice C. M., Ploss A.. ( 2013; ). Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. . J Immunol 191:, 1753–1764. [CrossRef] [PubMed]
    [Google Scholar]
  2. Borges A. A., Campos G. M., Moreli M. L., Souza R. L., Aquino V. H., Saggioro F. P., Figueiredo L. T.. ( 2006; ). Hantavirus cardiopulmonary syndrome: immune response and pathogenesis. . Microbes Infect 8:, 2324–2330. [CrossRef] [PubMed]
    [Google Scholar]
  3. Clement J., Maes P., Van Ranst M.. ( 2014; ). Hemorrhagic fever with renal syndrome in the New, and hantavirus pulmonary syndrome in the Old World: paradi(se)gm lost or regained?. Virus Res 187:, 55–58. [CrossRef] [PubMed]
    [Google Scholar]
  4. Cosgriff T. M.. ( 1991; ). Mechanisms of disease in hantavirus infection: pathophysiology of hemorrhagic fever with renal syndrome. . Rev Infect Dis 13:, 97–107. [CrossRef] [PubMed]
    [Google Scholar]
  5. Finsterbusch M., Voisin M. B., Beyrau M., Williams T. J., Nourshargh S.. ( 2014; ). Neutrophils recruited by chemoattractants in vivo induce microvascular plasma protein leakage through secretion of TNF. . J Exp Med 211:, 1307–1314. [CrossRef] [PubMed]
    [Google Scholar]
  6. Gavrilovskaya I. N., Gorbunova E. E., Mackow E. R.. ( 2010; ). Pathogenic hantaviruses direct the adherence of quiescent platelets to infected endothelial cells. . J Virol 84:, 4832–4839. [CrossRef] [PubMed]
    [Google Scholar]
  7. Gupta S., Braun M., Tischler N. D., Stoltz M., Sundström K. B., Björkström N. K., Ljunggren H. G., Klingström J.. ( 2013; ). Hantavirus-infection confers resistance to cytotoxic lymphocyte-mediated apoptosis. . PLoS Pathog 9:, e1003272. [CrossRef] [PubMed]
    [Google Scholar]
  8. Hammerbeck C. D., Hooper J. W.. ( 2011; ). T cells are not required for pathogenesis in the Syrian hamster model of hantavirus pulmonary syndrome. . J Virol 85:, 9929–9944. [CrossRef] [PubMed]
    [Google Scholar]
  9. Hu J., Nistal-Villán E., Voho A., Ganee A., Kumar M., Ding Y., García-Sastre A., Wetmur J. G.. ( 2010; ). A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells. . J Immunol 185:, 424–432. [CrossRef] [PubMed]
    [Google Scholar]
  10. Ishikawa F., Yasukawa M., Lyons B., Yoshida S., Miyamoto T., Yoshimoto G., Watanabe T., Akashi K., Shultz L. D., Harada M.. ( 2005; ). Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice. . Blood 106:, 1565–1573. [CrossRef] [PubMed]
    [Google Scholar]
  11. Ito M., Hiramatsu H., Kobayashi K., Suzue K., Kawahata M., Hioki K., Ueyama Y., Koyanagi Y., Sugamura K. et al. ( 2002; ). NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. . Blood 100:, 3175–3182. [CrossRef] [PubMed]
    [Google Scholar]
  12. Jaiswal S., Pearson T., Friberg H., Shultz L. D., Greiner D. L., Rothman A. L., Mathew A.. ( 2009; ). Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rγnull mice. . PLoS ONE 4:, e7251. [CrossRef] [PubMed]
    [Google Scholar]
  13. Jonsson C. B., Figueiredo L. T., Vapalahti O.. ( 2010; ). A global perspective on hantavirus ecology, epidemiology, and disease. . Clin Microbiol Rev 23:, 412–441. [CrossRef] [PubMed]
    [Google Scholar]
  14. Kanerva M., Mustonen J., Vaheri A.. ( 1998; ). Pathogenesis of puumala and other hantavirus infections. . Rev Med Virol 8:, 67–86. [CrossRef] [PubMed]
    [Google Scholar]
  15. Khaiboullina S. F., St Jeor S. C.. ( 2002; ). Hantavirus immunology. . Viral Immunol 15:, 609–625. [CrossRef] [PubMed]
    [Google Scholar]
  16. Kim S. S., Kumar P., Ye C., Shankar P.. ( 2012; ). Humanized mice for studying human leukocyte integrins in vivo. . Methods Mol Biol 757:, 509–521. [CrossRef] [PubMed]
    [Google Scholar]
  17. Koma T., Yoshimatsu K., Nagata N., Sato Y., Shimizu K., Yasuda S. P., Amada T., Nishio S., Hasegawa H., Arikawa J.. ( 2014; ). Neutrophil depletion suppresses pulmonary vascular hyperpermeability and occurrence of pulmonary edema caused by hantavirus infection in C.B-17 SCID mice. . J Virol 88:, 7178–7188. [CrossRef] [PubMed]
    [Google Scholar]
  18. Kramski M., Meisel H., Klempa B., Krüger D. H., Pauli G., Nitsche A.. ( 2007; ). Detection and typing of human pathogenic hantaviruses by real-time reverse transcription-PCR and pyrosequencing. . Clin Chem 53:, 1899–1905. [CrossRef] [PubMed]
    [Google Scholar]
  19. Krüger D. H., Schönrich G., Klempa B.. ( 2011; ). Human pathogenic hantaviruses and prevention of infection. . Hum Vaccin 7:, 685–693. [CrossRef] [PubMed]
    [Google Scholar]
  20. Lütteke N., Raftery M. J., Lalwani P., Lee M. H., Giese T., Voigt S., Bannert N., Schulze H., Krüger D. H., Schönrich G.. ( 2010; ). Switch to high-level virus replication and HLA class I upregulation in differentiating megakaryocytic cells after infection with pathogenic hantavirus. . Virology 405:, 70–80. [CrossRef] [PubMed]
    [Google Scholar]
  21. Mackow E. R., Gavrilovskaya I. N.. ( 2009; ). Hantavirus regulation of endothelial cell functions. . Thromb Haemost 102:, 1030–1041.[PubMed]
    [Google Scholar]
  22. Manfredi A. A., Rovere-Querini P., Maugeri N.. ( 2010; ). Dangerous connections: neutrophils and the phagocytic clearance of activated platelets. . Curr Opin Hematol 17:, 3–8. [CrossRef] [PubMed]
    [Google Scholar]
  23. Mestas J., Hughes C. C.. ( 2004; ). Of mice and not men: differences between mouse and human immunology. . J Immunol 172:, 2731–2738. [CrossRef] [PubMed]
    [Google Scholar]
  24. Peters C. J., Simpson G. L., Levy H.. ( 1999; ). Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. . Annu Rev Med 50:, 531–545. [CrossRef] [PubMed]
    [Google Scholar]
  25. Prescott J., Safronetz D., Haddock E., Robertson S., Scott D., Feldmann H.. ( 2013; ). The adaptive immune response does not influence hantavirus disease or persistence in the Syrian hamster. . Immunology 140:, 168–178. [CrossRef] [PubMed]
    [Google Scholar]
  26. Raftery M. J., Lalwani P., Krautkrämer E., Peters T., Scharffetter-Kochanek K., Krüger R., Hofmann J., Seeger K., Krüger D. H., Schönrich G.. ( 2014; ). β2 Integrin mediates hantavirus-induced release of neutrophil extracellular traps. . J Exp Med 211:, 1485–1497. [CrossRef] [PubMed]
    [Google Scholar]
  27. Raymond T., Gorbunova E., Gavrilovskaya I. N., Mackow E. R.. ( 2005; ). Pathogenic hantaviruses bind plexin-semaphorin-integrin domains present at the apex of inactive, bent αvβ3 integrin conformers. . Proc Natl Acad Sci U S A 102:, 1163–1168. [CrossRef] [PubMed]
    [Google Scholar]
  28. Schönrich G., Rang A., Lütteke N., Raftery M. J., Charbonnel N., Ulrich R. G.. ( 2008; ). Hantavirus-induced immunity in rodent reservoirs and humans. . Immunol Rev 225:, 163–189. [CrossRef] [PubMed]
    [Google Scholar]
  29. Schulze H., Shivdasani R. A.. ( 2005; ). Mechanisms of thrombopoiesis. . J Thromb Haemost 3:, 1717–1724. [CrossRef] [PubMed]
    [Google Scholar]
  30. Shultz L. D., Saito Y., Najima Y., Tanaka S., Ochi T., Tomizawa M., Doi T., Sone A., Suzuki N. et al. ( 2010; ). Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r γ(null) humanized mice. . Proc Natl Acad Sci U S A 107:, 13022–13027. [CrossRef] [PubMed]
    [Google Scholar]
  31. Strowig T., Gurer C., Ploss A., Liu Y. F., Arrey F., Sashihara J., Koo G., Rice C. M., Young J. W. et al. ( 2009; ). Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. . J Exp Med 206:, 1423–1434. [CrossRef] [PubMed]
    [Google Scholar]
  32. Terajima M., Ennis F. A.. ( 2011; ). T cells and pathogenesis of hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome. . Viruses 3:, 1059–1073. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.000087
Loading
/content/journal/jgv/10.1099/vir.0.000087
Loading

Data & Media loading...

Supplements

Supplementary Data



PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error