Host factors involved in chikungunya virus replication

Abstract

In this thesis the interplay of CHIKV with cellular (host) factors involved in its replication is addressed. An in-depth understanding of the interactions between the viral proteins and those of their host is required for the elucidation of molecular mechanisms underlying viral replication. A variety of proteins and pathways involved in CHIKV replication were identified in this thesis, and the role of a selection of those is described. First, the construction and characterization of a novel synthetic CHIKV full-length cDNA clone is described in chapter 2. In chapter3 we describe the identification of dozens of cellular factors and pathways that are potentially involved in CHIKV replication. Chapter 4 describes the response of the p38 MAPK and MEK/ERK signaling pathways in CHIKV-infected human cells. Chapter 5 describes the unexpected proviral role of stress granule components G3BP1 and G3BP2 early during CHIKV infection. In chapter 6 the inhibitory effect of a RIG-I agonist (5__pppRNA) on CHIKV and DENV replication is described. A low, noncytotoxic dose of 5__pppRNA stimulates RIG-I and leads to a robust antiviral response, potentially opening up therapeutic options against these important human pathogens. Chapter 7 discusses the findings described in this thesis, and places them in a broader context.