The innate immune response is a primary defense mechanism to combat microbial infection. In addition to providing necessary cues for the initiation of an adaptive immune response, activation of the innate signaling pathways triggers immediate and localized defensive activities. An important component of this response is the induction of proteins that have direct antiviral activities. Since viruses have developed molecular strategies to circumvent these activities, these restriction factor proteins impose strong constraints on viral evolution. Elucidate a global understanding of the molecular circuits that underlie these innate activities would provide opportunities for the development of novel antiviral therapeutics targeting this critical viral-host interface. Dengue (DENV) and West Nile (WNV) virus are members of the Flaviviridae family of positive strand RNA viruses. These viruses can activate Pattern Recognition Receptors, such as TLR3, TLR7, or RIG-I, which specifically respond to molecular signatures harbored by these viruses. Additionally, both dengue and West Nile virus harbor proteins that function to inhibit downstream type-1 interferon signaling (i.e. NS4B). This strongly suggests that activation of type-1 interferon induces the expression of target genes that directly impede the viruses'ability to effectively replicate. The goal of the proposal is to integrate two systems-level analytical technique, genome-wide mammalian genetic analysis and affinity purification mass spectrometry, to establish a global understanding of the host-pathogen molecular networks that underlie both innate immune-mediated restriction of viral replication, and viral countermeasures to these activities. A comprehensive, systems-level, analysis of these virus-host interactions will provide significant new molecular insight into the network infrastructure is regulated by the innate immune response to RNA virus infection.

Public Health Relevance

Human cells naturally harbor proteins that can combat virus infection, however, viruses often have developed molecular strategies to escape their activities. The goal of this proposal is to perform a comprehensive survey of human proteins that can block the replication of dengue and West Nile viruses, and to understand how they physically associate with these viruses. The results of this genome-wide analysis will provide new opportunities for the development of antiviral therapeutics that function by specifically reinstating the ability of our cells to combat viral infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Oregon Health and Science University
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