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 Europe . 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 disease. 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 mice. 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.

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

“…Interestingly, increased levels of ICAM1 protein were also reported by Fraisier and colleagues in CCHFV infection of HepG2 cells, and hypothesized to play a role in the oxidative stress response to the virus [51]. A limitation of our study is the use of the prototypical IbAr 10200 strain, which has undergone significant passaging and lab adaptation and is likely more attenuated than currently circulating strains [9,52]. Although use of this strain permits comparison to other laboratory findings (due to it's widespread use in Western labs), further studies to compare transcriptomic profiles from CCHFV strains associated with low mortality, such as AP92, to more virulent isolates, performed in both cell lines and primary cell cultures are needed to provide additional insight into viral pathogenesis [53][54][55].…”

“…For example, the virus has been shown to replicate to higher titers in Huh7 cells, compared to other non-hepatocytes lines [6][7][8]. Additionally, the highest viral titers were observed in the livers of STAT-1 knockout mice infected with CCHFV, and in the recently published cynomolgus macaque model, hepatic necrosis was noted [9,10]. Furthermore, clinical findings also support the role of the liver in disease, as it is an early target organ for CCHFV [11], and its involvement following infection is associated the elevation of AST and ALT correlating with poor prognosis [11][12][13].…”

Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever

“…Ideally, an immunocompetent, larger animal model is greatly needed in the CCHF field to further test the array of CCHFV experimental vaccines which have shown promise in these mouse models. A promising step forward appears to be the nonhuman primate disease model that has been recently developed 59 . However, CCHF in this model appears strain and challenge route dependent.…”

Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in Ifnar-/- mice

“…As a high-consequence pathogen with an expanding geographic range, CCHFV is increasingly recognized as a growing public health concern [4]. The availability of disease models remains a challenge in CCHFV research; lethal models are currently limited to interferon-(IFN) deficient (Stat-1 -/and Ifnar -/-) mice [5][6][7], and humanized (Hu-NSG-SGM3) [8] mice, although disease has been recently described in cynomolgus macaques [9]. Despite their limitations, IFN-deficient mice have been instrumental in facilitating the study of CCHFV pathogenesis in vivo.…”