Characterization of a human-specific positive regulator of flavivirus infection

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Project Summary/Abstract Flaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV) or Dengue virus (DENV) are cause of great health and economic concerns worldwide. YFV is the prototypical member of the flavivirus genus, and one of the first human pathogenic viruses that has been identified. Despite the development of a very potent vaccine in the 1930’s, YFV still represents a real theat. Recent outbreaks in Angola and Brazil, over the past two years, occurred in areas with low vaccination coverage. These resurgence events have exemplified the threat and have highlighted the need for the protection of an estimated 400 to 500 million people worldwide. Facing a significant vaccine shortage, fractional doses of vaccine are now used during vaccination campaigns despite no/limited evidence of long-term protection, hence underscoring the urgent necessity of developing novel strategies to clinically manage future YFV outbreaks. Our knowledge of the YFV infectious cycle in vitro and in vivo is extremely limited which has ultimately hampered the development of specific therapies to treat YFV infection, as none is currently available. I recently identified a novel host regulator of YFV infection in human cells that is required for effective YFV infection and replication in vitro. As it is not expressed in mice, this factor could also contribute to the human/primate-specific tropism of YFV. Building on a robust set of preliminary data, I hypothesize that this factor regulates RNA replication or protein translation through direct binding to viral elements. In Aim 1, I will explore the mechanisms by which this factor regulates the replication of the YFV vaccine strain YFV-17D in vitro as well as the host and virus determinants that govern such regulation. In Aim 2, I will determine the role of this factor on the replication of a virulent YFV strain, YFV-Asibi, as well as of other flaviviruses of interest such as ZIKV and DENV. I will also seek to explore the role of this factor using more relevant cell culture system such as primary human hepatocytes by using specific inhibitor of this factor. In Aim 3, I will use a humanized mouse model I recently developed and that is permissive to YFV infection to evaluate the role of this factor on YFV-Asibi and YFV-17D replication in vivo, by treating mice with specific inhibitor of the identified host factor. Altogether, my strong expertise in studying YFV virus in vitro and in vivo, combined with the different viral tracking tools and in vivo models I have previously developed, position me very well to conduct the proposed research. This research could provide novel avenues for the specific treatment of YFV infection and enhance our understanding of the host-pathogen interactions that define flavivirus pathogenicity. This K22 Career Transition Award will help me achieve my scientific and career goals, which consist of transitioning toward an independent assistant professor position and establishing an independent NIH-funded research program aiming at elucidating the mechanisms of flavivirus pathogenicity.