Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is endemic in Europe, Asia, and Africa. The geographic distribution of CCHFV is expanding as Hyalomma ticks, the main carriers of the virus, migrate northward. Infection with CCHFV initially manifests with non-specific symptoms including fever, muscle pains, and nausea that may progress into a hemorrhagic phase characterized by severe bleeding throughout the body. The case fatality rate is reported to range between 9-50%. With increasing numbers of humans at risk, further understanding of how the virus causes disease is essential for developing effective therapeutics. Studies investigating the host and viral determinants of pathogenesis, however, have been constrained due to mouse models requiring mice to be deficient in initial innate immune responses to manifest CCHFV disease symptoms after infection. However, we have recently developed a mouse-adapted CCHFV (MA-CCHFV) which presents with disease similar to human CCHFV cases in fully immunocompetent mice. We hypothesize that adaptive mutations in MA-CCHFV have enabled the virus to overcome mouse innate immunity and cause disease in immunocompetent mice.
CCHFV is an RNA virus with three genomic segments. The S segment encodes the nucleoprotein (NP) and a non-structural protein (NSs) while the M segment encodes a large multi-unit protein which is later cleaved into two structural glycoproteins and three non-structural proteins. The L segment has largely unknown function(s) but does encode a protein required for viral replication. Compared to parental strain CCHFV-Hoti, MA-CCHFV has 6 mutations which result in changes to proteins encoded by the virus. Two mutations occur in the NP, one in the NSs, two in the M segment non-structural proteins GP38 and NSm and two in the viral L protein. These mutations likely indicate key proteins CCHFV uses as virulence factors to cause severe disease. To determine the role of these adaptations, we are examining the responses of human and mouse cell lines to infection with parental and MA-CCHFV strains. In addition, we can express the viral proteins independently of the virus to isolate the specific roles of these proteins and understand how they affect the initial immune responses in mouse cells. Understanding how these mutated proteins uniquely interact with the mouse immune system will help identify the host and viral determinants of CCHFV-induced disease. This will support new avenues of focus in CCHFV research to develop effective therapeutics and vaccines.
This research is funded by the Intramural Research Program, NIAID, NIH