Diversity, Replication, Pathogenicity and Cell Biology of Crimean Congo Hemorrhagic Fever Virus
Final addendum rept. 16 Sep 2009-30 Sep 2010
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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This research project was a result of a collaboration between three research groups aimed at elucidating basic replication processes of CCHFV with the expected outcome of providing basic research reagents and establishing the foundation of knowledge necessary for discovery of vaccines and antiviral therapeutics for Crimean Congo hemorrhagic fever. Our major findings during the total period of support were the following We have cloned and expressed all proteins of CCHFV. We found that the protease activity associated with the N-terminal of the L protein is responsible for overcoming innate immune responses mediated by ubiquitin and by the ubiquitin-like molecule ISG15. We have identified inhibitors of this protease, and solved its structure. We have characterized in detail the processing of the G protein and the expression of the NSm protein of CCHFV, and developed constructs with fusogenic activity based on expression of the G ORF. We have successfully passaged CCHFV 18 times in SCID mice and conducted preliminary studies in macaques. We have confirmed that infection of STAT1 -- mice with CCHFV results in lethal disease, opening the possibility of using a mouse model of this virus. Our results have provided novel insights on the molecular biology of this highly pathogenic human virus and opened new avenues for the discovery of CCHFV antivirals.
- Medicine and Medical Research