DELINEATING THE MOLECULAR MECHANISMS OF CHIKUNGUNYA VIRUS EVASION OF THE HOST CELLULAR PROCESSES

Abstract

CHIKUNGUNYA VIRUS (CHIKV) INFECTS MILLIONS OF PEOPLE WORLDWIDE EACH YEAR, CAUSING CHIKUNGUNYA FEVER, AN ACUTE FEBRILE ILLNESS CHARACTERIZED IN HUMANS BY RASH AND ARTHRITIS. CHIKV REPLICATES PRODIGIOUSLY IN INFECTED PATIENTS AND IN VITRO IN MAMMALIAN CELLS, SUGGESTING SOME LEVEL OF CONTROL OVER THE HOST CELLULAR TRANSLATIONAL MACHINERY, WHICH IS RESPONSIBLE FOR SENSING AND APPROPRIATELY DIRECTING THE CELL?S FATE THROUGH THE UNFOLDED PROTEIN RESPONSE (UPR). UPR IS A CELLULAR RESPONSE THAT REGULATES THE FATE OF MIS/UN-FOLDED PROTEINS IN THE ER AND HAS THE POTENTIAL TO LIMIT VIRUS REPLICATION. IN THIS STUDY WE HAVE IDENTIFIED NOVEL MECHANISMS THAT CHIKV UTILIZES TO MODULATE UPR TO MAINTAIN ITS ROBUST REPLICATION. FURTHERMORE, WE ALSO SHOW THAT DRUGS BLOCKING CHIKV MODULATION OF UPR CAN INHIBIT CHIKV REPLICATION AND INFLAMMATION IN CELL CULTURE OR INFECTED ANIMALS. THIS DETAILED STUDY OF THE UNDERLYING MOLECULAR MECHANISMS OF CHIKV AND HOST UPR INTERACTIONS MAY PROVIDE A PLATFORM TO DEVELOP