The Molecular Determinants of Virulence in Crimean-Congo Hemorrhagic Fever Virus

Abstract

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick borne nairovirus that is capable of causing a severe hemorrhagic disease in humans. The spectrum of disease caused by infection with CCHFV is extremely broad, with clinical presentations ranging from subclinical infection or a mild febrile illness to severe and highly fatal hemorrhagic disease in the most severe cases. Where a particular case will fall upon this spectrum of clinical severity is determined by a complex interplay of many host- and virus-specific variables. Recent developments in reverse genetics and animal models have led to a proliferation of studies on the molecular pathogenesis of CCHFV. However, there is a dearth of review-style studies that have collected all of the existing data on the subject in order to paint a clear picture of where we currently stand regarding our knowledge of CCHFV and how it causes disease in humans. In this narrative review, I attempt to answer the question of how each protein encoded by CCHFV influences where a particular case will fall on the spectrum of clinical severity. Specifically, I review virulence-enhancing properties of CCHFV-encoded proteins such as the ability to modulate and antagonize the interferon response, inflict direct damage upon host tissue, and disrupt wound healing, among others. The purpose of this narrative review is two-fold: first, I aim to present the state of our current knowledge regarding the molecular basis of virulence in CCHFV with a particular emphasis on data from recent studies utilizing animal models and reverse genetics. Second, I comprehensively outline gaps in knowledge and open questions that will be useful to generate hypotheses for future research.