Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne Nairovirus that causes severe hemorrhagic fever with a mortality rate of up to 30% in certain outbreaks worldwide. The virus has wide endemic distribution. There is no effective antiviral therapeutic or FDA approved vaccine for this zoonotic viral illness. The multifunctional CCHFV nucleocapsid protein (N protein) plays a crucial role in the establishment of viral infection and is an important structural component of the virion. Here we show that CCHFV N protein has a distant RNA-binding site in the stalk domain that specifically recognizes the vRNA panhandle, formed by the base pairing of complementary nucleotides at the 5' and 3' termini of the vRNA genome. Using multiple approaches, including filter-bonding analysis, GFP reporter assay, and biolayer interferometry we observed an N protein-panhandle interaction both in vitro and in vivo The purified WT CCHFV N protein and the stalk domain also recognize the vRNA panhandle of hazara virus, another Nairovirus in the family Bunyaviridae, demonstrating the genus-specific nature of N protein-panhandle interaction. Another RNA-binding site was identified at the head domain of CCHFV N protein that nonspecifically recognizes the single strand RNA (ssRNA) of viral or nonviral origin. Expression of CCHFV N protein stalk domain active in panhandle binding, dramatically inhibited the hazara virus replication in cell culture, illustrating the role of N protein-panhandle interaction in Nairovirus replication. Our findings reveal the stalk domain of N protein as a potential target in therapeutic interventions to manage CCHFV disease.
Highlights
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne Nairovirus that causes severe hemorrhagic fever with a mortality rate of up to 30% in certain outbreaks worldwide
Using four independent binding approaches, we previously demonstrated that N protein binds to the panhandle RNA structure composed of partially complementary 30 nucleotides from both 5Ј and 3Ј termini of CCHFV S-segment viral RNA (vRNA) (Fig. 1B), with the same affinity as full-length vRNA (Kd ϳ 42 nM)
Using the X-ray crystal structure of the CCHFV N protein, we modeled the 3D structure of CCHFV N protein
Summary
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne Nairovirus that causes severe hemorrhagic fever with a mortality rate of up to 30% in certain outbreaks worldwide. The purified WT CCHFV N protein and the stalk domain recognize the vRNA panhandle of hazara virus, another Nairovirus in the family Bunyaviridae, demonstrating the genus-specific nature of N protein-panhandle interaction. Another RNA-binding site was identified at the head domain of CCHFV N protein that nonspecifically recognizes the single strand RNA (ssRNA) of viral or nonviral origin. Causes severe hemorrhagic fever with a mortality rate of 5 to 30% in more than 30 countries worldwide [1,2,3,4] To date, this zonotic viral illness has been reported in the Balkans, Eastern Europe, Central Asia, Turkey, China, Africa, and the Middle East [5,6,7,8,9].
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