title: Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo.
abstract: The global emergence of Chikungunya virus (CHIKV) infection is alarming and currently there is no licensed vaccine or antiviral treatment available to mitigate this disease. CHIKV infection typically results in high viral load with an outcome of high fever, skin rashes, muscle pain, and sequelae of prolonged arthritis, which occurs in >90% of the infected cases. In this study, using biochemical pull-downs, mass-spectrometry, and microscopic imaging techniques, we have identified novel interactions between CHIKV nsP3 or nsP4 proteins with the host stress-pathway chaperone HSP-90 protein. Indeed, silencing of HSP-90 transcripts using siRNA disrupts CHIKV replication in cultured cells. Furthermore, drugs targeting HSP-90, such as commercially available geldanamycin, as well as other specific HSP-90 inhibitor drugs that had been obtained from a purinome mining approach (HS-10 and SNX-2112) showed dramatic reduction in viral titers and reduced inflammation in a CHIKV mouse model of severe infection and musculopathy. The detailed study of the underlying molecular mechanism of these viral and host protein interactions may provide a platform to develop novel therapeutics against CHIKV infection.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Department of Microbiology, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Abhay P S
authors.initials: AP
authors.lastname: Rathore
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, United States; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Haystead
authors.affiliation: Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
authors.forename: Pratyush K
authors.initials: PK
authors.lastname: Das
authors.affiliation: Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Mah-Lee
authors.initials: ML
authors.lastname: Ng
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Department of Microbiology, National University of Singapore, Singapore 117597, Singapore. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D018354:Alphavirus Infections / Q000188:drug therapy / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002498:Centrifugation; D002646:Chikungunya virus / Q000502:physiology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D061848:Optical Imaging; D011485:Protein Binding; D025941:Protein Interaction Mapping; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D017361:Viral Nonstructural Proteins
keywords: CHIKV mouse model; CHIKV nsP3; CHIKV nsP4; Geldanamycin; HSP-90; Protein interactions