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A cynomolgus macaque model for Crimean–Congo haemorrhagic fever

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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Fig. 1: Clinical parameters for CCHFV-infected cynomolgus macaques.
Fig. 2: Profile of immune factors by infection route in CCHFV-infected cynomolgus macaques.
Fig. 3: Histopathology, immunohistochemistry and in situ hybridization (viral genomic RNA) of the liver from CCHFV-infected cynomolgus macaques.
Fig. 4: Profile of CCHF disease in cynomolgus macaques.

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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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Correspondence to Heinz Feldmann.

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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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