Abstract
Crimean–Congo haemorrhagic fever (CCHF) is the most medically significant tick-borne disease, being widespread in the Middle East, Asia, Africa and parts of Europe1. Increasing case numbers, westerly movement and broadly ranging case fatality rates substantiate the concern of CCHF as a public health threat. Ixodid ticks of the genus Hyalomma are the vector for CCHF virus (CCHFV), an arbovirus in the genus Orthonairovirus of the family Nairoviridae. CCHFV naturally infects numerous wild and domestic animals via tick bite without causing obvious disease2,3. Severe disease occurs only in humans and transmission usually happens through tick bite or contact with infected animals or humans. The only CCHF disease model is a subset of immunocompromised mice4,5,6. Here, we show that following CCHFV infection, cynomolgus macaques exhibited hallmark signs of human CCHF with remarkably similar viral dissemination, organ pathology and disease progression. Histopathology showed infection of hepatocytes, endothelial cells and monocytes and fatal outcome seemed associated with endothelial dysfunction manifesting in a clinical shock syndrome with coagulopathy. This non-human primate model will be an invaluable asset for CCHFV countermeasures development.
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References
Bente, D. A. et al Crimean–Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Antiviral Res. 100, 159–189 (2013).
Hoogstraal, H. The epidemiology of tick-borne Crimean–Congo hemorrhagic fever in Asia, Europe, and Africa. J. Med. Entomol. 15, 307–417 (1979).
Spengler, J. R. et al. A chronological review of experimental infection studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus. Antiviral Res. 135, 31–47 (2016).
Bente, D. A. et al. Pathogenesis and immune response of Crimean–Congo hemorrhagic fever virus in a STAT-1 knockout mouse model. J. Virol. 84, 11089–11100 (2010).
Bereczky, S. et al. Crimean–Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. J. Gen. Virol. 91, 1473–1477 (2010).
Zivcec, M. et al. Lethal Crimean-Congo hemorrhagic fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy. J. Infect. Dis 207, 1909–1921 (2013).
Cevik, M. A. et al. Viral load as a predictor of outcome in Crimean–Congo hemorrhagic fever. Clin. Infect. Dis. 45, e96–e100 (2007).
Onguru, P. et al. Coagulopathy parameters in patients with Crimean–Congo hemorrhagic fever and its relation with mortality. J. Clin. Lab. Anal. 24, 163–166 (2010).
Duh, D. et al. Viral load as predictor of Crimean–Congo hemorrhagic fever outcome. Emerg. Infect. Dis. 13, 1769–1772 (2007).
Whitehouse, C. A. Crimean–Congo hemorrhagic fever. Antiviral Res. 64, 145–160 (2004).
Ergonul, O. Crimean–Congo haemorrhagic fever. Lancet Infect. Dis. 6, 203–214 (2006).
Kubar, A. et al. Prompt administration of Crimean–Congo hemorrhagic fever (CCHF) virus hyperimmunoglobulin in patients diagnosed with CCHF and viral load monitorization by reverse transcriptase-PCR. Jpn J. Infect. Dis. 64, 439–443 (2011).
Swanepoel, R. et al. The clinical pathology of Crimean–Congo hemorrhagic fever. Rev. Infect. Dis 11(Suppl.4), S794–S800 (1989).
Vorou, R., Pierroutsakos, I. N. & Maltezou, H. C. Crimean–Congo hemorrhagic fever. Curr. Opin. Infect. Dis. 20, 495–500 (2007).
Soares-Weiser, K., Thomas, S., Thomson, G. & Garner, P. Ribavirin for Crimean–Congo hemorrhagic fever: systematic review and meta-analysis. BMC Infect. Dis. 10, 207 (2010).
Keshtkar-Jahromi, M. et al Crimean–Congo hemorrhagic fever: current and future prospects of vaccines and therapies. Antiviral Res. 90, 85–92 (2011).
Fagbami, A. H., Tomori, O., Fabiyi, A. & Isoun, T. T. Experimantal Congo virus (Ib -AN 7620) infection in primates. Virologie 26, 33–37 (1975).
Smirnova, S. E. A comparative study of the Crimean hemorrhagic fever-Congo group of viruses. Arch. Virol. 62, 137–143 (1979).
Fajs, L. et al. Molecular epidemiology of Crimean–Congo hemorrhagic fever virus in Kosovo. PLoS Negl. Trop. Dis. 8, e2647 (2014).
Brining, D. L. et al. Thoracic radiography as a refinement methodology for the study of H1N1 influenza in cynomologus macaques (Macaca fascicularis). Comp. Med. 60, 389–395 (2010).
Causey, O. R., Kemp, G. E., Madbouly, M. H. & David-West, T. S. Congo virus from domestic livestock, African hedgehog, and arthropods in Nigeria. Am. J. Trop. Med. Hyg. 19, 846–850 (1970).
Duh, D. et al. The complete genome sequence of a Crimean–Congo hemorrhagic fever virus isolated from an endemic region in Kosovo. Virol. J. 5, 7 (2008).
Safronetz, D. et al. Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques. Proc. Natl Acad. Sci. USA 111, 7114–7119 (2014).
Burt, F. J. et al. Immunohistochemical and in situ localization of Crimean–Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch. Pathol. Lab. Med. 121, 839–846 (1997).
Ergonul, O. et al. Cytokine response in Crimean–Congo hemorrhagic fever virus infection. J. Med. Virol. 89, 1707–1713 (2017).
Kaya, S. et al. Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean–Congo hemorrhagic fever. BMC Infect. Dis. 14, 416 (2014).
Papa, A. et al. Cytokines as biomarkers of Crimean–Congo hemorrhagic fever. J. Med. Virol. 88, 21–27 (2016).
Saksida, A., Wraber, B. & Avsic-Zupanc, T. Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome. BMC Infect. Dis. 11, 142 (2011).
Ergonul, O., Tuncbilek, S., Baykam, N., Celikbas, A. & Dokuzoguz, B. Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-α in patients with Crimean-Congo hemorrhagic fever. J. Infect. Dis. 193, 941–944 (2006).
Wang, F. et al. RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J. Mol. Diagn. 14, 22–29 (2012).
Acknowledgements
We thank the staff of the Rocky Mountain Veterinary Branch, Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) for assistance with animal care and clinical and pathological veterinary services, and Atsushi Okumura for veterinary expertise throughout the study. We would also like to thank the members of the Visual and Medical Arts (DIR, NIAID, NIH) for aid in figure development. This work was funded by the Intramural Research Programme of the NIAID, NIH.
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E.H. and H.F. planned the study. E.H., F.F., M.Z., P.W.H., G.S, D.P.S. and D.S. conducted the non-human primate work. E.H., F.F., D.W.H., P.W.H., G.S., D.P.S. and T.T. acquired the data. E.H., P.W.H., G.S., D.H., M.K., T.A.-Z. and H.F. analysed and interpreted the data. M.K. and T.A.-Z. provided critical reagents. E.H. and H.F. wrote the first draft. All authors reviewed, edited and approved the paper.
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Haddock, E., Feldmann, F., Hawman, D.W. et al. A cynomolgus macaque model for Crimean–Congo haemorrhagic fever. Nat Microbiol 3, 556–562 (2018). https://doi.org/10.1038/s41564-018-0141-7
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DOI: https://doi.org/10.1038/s41564-018-0141-7
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