Virus-host interaction and molecular pathogenesis of Crimean Congo haemorrhagic fever

Crimean Congo haemorrhagic fever virus (CCHFV) is a negative-strand RNA virus belonging to the genus Nairovirus of the Bunyaviridae family. The virus is present in about 30 countries and it is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. In particular, ticks of the genus Hyalomma seem to be the principal vectors and play an important role as a natural reservoir. Human infections begin with nonspecific febrile symptoms that progress to a serious haemorrhagic syndrome with a high case fatality rate. To date, no specific treatment or vaccine are available and prevention of human disease depends merely on avoiding bites from infected ticks and contact with infected blood or tissues. Despite a wide distribution, the pathogenesis of CCHF remains poorly understood, because of limited human pathology and the need for biosafety level 4 facilities. The major pathological abnormalities of CCHF are alteration of vascular barrier function and haemorrhage. Endothelial damage can contribute to coagulopathy but it is still unknown whether vascular dysfunction is due to a direct effect of virus on the endothelial cells or to a consequence of a cytokine storm. Indeed, elevated levels of pro-inflammatory mediators (such as TNF-α, IL-6, IL-10) and serum markers of vascular activation (sICAM-1 and sVCAM-1) have been detected in fatal CCHF cases. In vitro experiments in human target cell lines have shown that CCHFV induces apoptosis late post infection and the release of TNF-α, IL-6 and IL-8, with the activation of endothelial cells. Although CCHFV is sensitive to type I interferons in vitro at the early stage of infection, IFN has no significant activity against an already established CCHFV infection, suggesting that CCHFV strongly counteracts IFN signalling. It has been demonstrated that CCHFV employs a range of strategies to evade and counteract the innate immune response to establish viral infection. Despite an improved knowledge of the viral biology and a better understanding of the disease clinical aspects, there are still many gaps to be filled. In this context, our research is focused on the study of vector-virus interaction and on the development of innovative vaccine approaches based on virus like particles/recombinant viruses for the control and prevention of human disease.