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Abstract

Dengue is a mosquito-borne disease caused by four related but distinct dengue viruses, DENV-1 to DENV-4. Dengue is endemic in most tropical countries, and over a third of the world's population is at risk of being infected. Although the global burden is high, no vaccine or antiviral is licensed to combat this disease. An obstacle complicating dengue research is the lack of animal challenge models that mimic human disease. Advances in immunocompromised murine infection models resulted in development of lethal DENV-2, DENV-3 and DENV-4 models in AG129 mice, which are deficient in both the IFN-α/β receptor (IFN-α/βR) and the IFN-γ receptor (IFN-γR). These models mimic features of dengue disease in humans. Here, we characterized lethal infection of AG129 mice by DENV-4 strain TVP-376 and found that AG129 mice developed clinical signs of illness and high viral loads in multiple tissues and succumbed 5 days after infection. Moreover, the splenic and hepatic histopathology of TVP-376-infected mice demonstrated the presence of cell activation and destruction of tissue architecture. Furthermore, infected mice had heightened levels of circulating cytokines. Comparison of the virulence phenotypes of DENV-4 strain TVP-376 and DENV-2 strain D2S10 revealed that TVP-376-induced mortality occurred in the absence of both IFN-α/βR and IFN-γR signalling, but not with intact signalling from the IFN-γR, whereas D2S10 required the absence of IFN-α/βR signalling only, indicating that it is more virulent than TVP-376. In conclusion, TVP-376 is lethal in AG129 mice, and this model provides a useful platform to investigate vaccine candidates and antivirals against DENV-4.

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2015-10-01
2021-10-27
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References

  1. Aguirre S., Maestre A.M., Pagni S., Patel J.R., Savage T., Gutman D., Maringer K., Bernal-Rubio D., Shabman R.S., other authors. 2012; DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS Pathog 8:e1002934 [View Article][PubMed]
    [Google Scholar]
  2. Ashour J., Morrison J., Laurent-Rolle M., Belicha-Villanueva A., Plumlee C.R., Bernal-Rubio D., Williams K.L., Harris E., Fernandez-Sesma A., other authors. 2010; Mouse STAT2 restricts early dengue virus replication. Cell Host Microbe 8:410–421 [View Article][PubMed]
    [Google Scholar]
  3. Atrasheuskaya A., Petzelbauer P., Fredeking T.M., Ignatyev G. 2003; Anti-TNF antibody treatment reduces mortality in experimental dengue virus infection. FEMS Immunol Med Microbiol 35:33–42 [View Article][PubMed]
    [Google Scholar]
  4. Balsitis S.J., Williams K.L., Lachica R., Flores D., Kyle J.L., Mehlhop E., Johnson S., Diamond M.S., Beatty P.R., Harris E. 2010; Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6:e1000790 [View Article][PubMed]
    [Google Scholar]
  5. Bhatt S., Gething P.W., Brady O.J., Messina J.P., Farlow A.W., Moyes C.L., Drake J.M., Brownstein J.S., Hoen A.G., other authors. 2013; The global distribution and burden of dengue. Nature 496:504–507 [View Article][PubMed]
    [Google Scholar]
  6. Bozza F.A., Cruz O.G., Zagne S.M.O., Azeredo E.L., Nogueira R.M.R., Assis E.F., Bozza P.T., Kubelka C.F. 2008; Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 8:86 [View Article][PubMed]
    [Google Scholar]
  7. Chen H.-W., King K., Tu J., Sanchez M., Luster A.D., Shresta S. 2013; The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus. J Immunol 191:4194–4201 [View Article][PubMed]
    [Google Scholar]
  8. Fuchs J., Chu H., O'Day P., Pyles R., Bourne N., Das S.C., Milligan G.N., Barrett A.D., Partidos C.D., Osorio J.E. 2014; Investigating the efficacy of monovalent and tetravalent dengue vaccine formulations against DENV-4 challenge in AG129 mice. Vaccine 32:6537–6543 [View Article][PubMed]
    [Google Scholar]
  9. Green A.M., Beatty P.R., Hadjilaou A., Harris E. 2014; Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol 426:1148–1160 [View Article][PubMed]
    [Google Scholar]
  10. Johnson A.J., Roehrig J.T. 1999; New mouse model for dengue virus vaccine testing. J Virol 73:783–786
    [Google Scholar]
  11. Messina J.P., Brady O.J., Scott T.W., Zou C., Pigott D.M., Duda K.A., Bhatt S., Katzelnick L., Howes R.E., other authors. 2014; Global spread of dengue virus types: mapping the 70 year history. Trends Microbiol 22:138–146 [View Article][PubMed]
    [Google Scholar]
  12. Milligan G.N., Sarathy V.V., Infante E., Li L., Campbell G.A., Beatty P.R., Harris E., Barrett A.D., Bourne N. 2015; A dengue virus type 4 model of disseminated lethal infection in AG129 mice. PLoS One 10:e0125476 [View Article][PubMed]
    [Google Scholar]
  13. Mota J., Rico-Hesse R. 2009; Humanized mice show clinical signs of dengue fever according to infecting virus genotype. J Virol 83:8638–8645 [View Article][PubMed]
    [Google Scholar]
  14. Orozco S., Schmid M.A., Parameswaran P., Lachica R., Henn M.R., Beatty R., Harris E. 2012; Characterization of a model of lethal dengue virus 2 infection in C57BL/6 mice deficient in the alpha/beta interferon receptor. J Gen Virol 93:2152–2157 [View Article][PubMed]
    [Google Scholar]
  15. Perry S.T., Prestwood T.R., Lada S.M., Benedict C.A., Shresta S. 2009; Cardif-mediated signaling controls the initial innate response to dengue virus in vivo. J Virol 83:8276–8281 [View Article][PubMed]
    [Google Scholar]
  16. Perry S.T., Buck M.D., Lada S.M., Schindler C., Shresta S. 2011; STAT2 mediates innate immunity to dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS Pathog 7:e1001297 [View Article][PubMed]
    [Google Scholar]
  17. Prestwood T.R., Morar M.M., Zellweger R.M., Miller R., May M.M., Yauch L.E., Lada S.M., Shresta S. 2012; Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice. J Virol 86:12561–12570 [View Article][PubMed]
    [Google Scholar]
  18. Rothman A.L. 2011; Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11:532–543 [View Article][PubMed]
    [Google Scholar]
  19. Sarathy V.V., White M., Li L., Gorder S.R., Pyles R.B., Campbell G.A., Milligan G.N., Bourne N., Barrett A.D.T. 2015; A lethal murine infection model for dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease. J Virol 89:1254–1266 [View Article][PubMed]
    [Google Scholar]
  20. Shresta S., Kyle J.L., Snider H.M., Basavapatna M., Beatty P.R., Harris E. 2004; Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical. J Virol 78:2701–2710 [View Article][PubMed]
    [Google Scholar]
  21. Shresta S., Sharar K.L., Prigozhin D.M., Beatty P.R., Harris E. 2006; Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 80:10208–10217 [View Article][PubMed]
    [Google Scholar]
  22. Simmons C.P., Farrar J.J., van Vinh Chau N., Wills B. 2012; Dengue. N Engl J Med 366:1423–1432 [View Article][PubMed]
    [Google Scholar]
  23. Srikiatkhachorn A., Green S. 2010; Markers of dengue disease severity. Curr Top Microbiol Immunol 338:67–82 [View Article]
    [Google Scholar]
  24. Sukupolvi-Petty S., Brien J.D., Austin S.K., Shrestha B., Swayne S., Kahle K., Doranz B.J., Johnson S., Pierson T.C., other authors. 2013; Functional analysis of antibodies against dengue virus type 4 reveals strain-dependent epitope exposure that impacts neutralization and protection. J Virol 87:8826–8842 [View Article][PubMed]
    [Google Scholar]
  25. Tan G.K., Ng J.K.W., Trasti S.L., Schul W., Yip G., Alonso S. 2010; A non mouse-adapted dengue virus strain as a new model of severe dengue infection in AG129 mice. PLoS Negl Trop Dis 4:e672 [View Article][PubMed]
    [Google Scholar]
  26. Yauch L.E., Shresta S. 2008; Mouse models of dengue virus infection and disease. Antiviral Res 80:87–93 [View Article][PubMed]
    [Google Scholar]
  27. Zellweger R.M., Shresta S. 2014; Mouse models to study dengue virus immunology and pathogenesis. Front Immunol 5:151 [View Article][PubMed]
    [Google Scholar]
  28. Zellweger R.M., Prestwood T.R., Shresta S. 2010; Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7:128–139 [View Article][PubMed]
    [Google Scholar]
  29. Zompi S., Harris E. 2012; Animal models of dengue virus infection. Viruses 4:62–82 [View Article][PubMed]
    [Google Scholar]
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