A cross-sectional approach to identification & interrogation of adaptive & functional mutations affecting CCHFV replication & pathogenicity in humans

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Crimean-Congo haemorrhagic fever (CCHF) is the most widespread tick-associated viral haemorrhagic disease. Clinical presentation of the disease ranges from non-symptomatic to severe haemorrhage fever leading to a high degree of morbidity and death. The agent of CCHF is the virus CCHF orthonairovirus (CCHFV), a member of the Nairoviridae family with a tripartite negative sense RNA genome. Segment reassortment and recombination between and within segments in addition to genetic drift brought about by the high error rate of the viral polymerase, provides an enormous diversity of genome opportunities, which enables these viruses to adapt, exploit varying conditions and new environmental niches. Within this broad genomic diversity and range in clinical presentation, we expect that genetic determinants of the virus contribute to its pathogenicity in humans. Although no clear evidence is available.In this research proposal, we aim to determine the virological significance of genetic diversities of CCHFV in human pathogenicity. We hypothesize that CCHFV in humans undergoes distinct genetic variation after introduction from tick or vertebrate hosts, in order to adapt to this new environment, and that the resulting mutations modify viral replication capacities and subsequently virulence in humans.To this end, the project will focus on the following work packages; 1. Identification of amino acid mutations that have occurred specifically in human isolates. 2. Tracking the emergence of mutations on CCHFV in human cases. 3. Experimental evaluation of the identified mutations.These results will provide insight into a better understanding of the molecular mechanisms of pathogenicity associated with CCHFV in humans. Additionally, sequence data from various tick samples and human infections will support a better understanding of CCHFV evolution during infection in human and circulation in host ticks. Furthermore, these results will provide information for the potential targeting of vaccines and antivirals against CCHFV.