Alpha Omega Alpha Honor Medical Society

2011 Research Abstract

How does dengue virus evade the immune system and establish an infection? Identification of host factors in human primary monocytes and monocyte-derived dendritic cells that enhance or suppress dengue virus infection

Investigator: Timothy Savage

Mentor: Dr. Ana Fernandez-Sesma, PhD

Dengue virus is the most prevalent arthropod-borne virus in the world, with an estimated 50-100 million people infected each year and no available vaccine or antiviral treatments. Characterized by a febrile illness, muscle, bone, and retro-orbital pain, dengue virus can be a devastating disease. 500,000 patients a year, disproportionately children, are afflicted with Severe Dengue, which can feature hemorrhage and shock on top of the aforementioned symptoms and carries a mortality rate of 1-20% depending on available treatment. Vaccines and antivirals are urgently needed, but in order to generate targeted therapeutics a better understanding of dengue virus-host interactions is needed. Our study aimed to identify host factors that either restricted or enhanced dengue virus replication with the aim of elucidating host-viral interactions and identifying targets for therapeutic intervention. After a proteomic analysis of primary human monocytic cells infected with dengue virus, we identified numerous proteins that changed in abundance following an infection. For one of these proteins, RNH1, we generated a stable cell line knocking it down. Following dengue virus infection in these cells, we demonstrated that RNH1 is a potent restriction factor of dengue virus replication, findings that were replicated with hepatitis C virus, but not with yellow fever virus. This data suggests that the control of viral replication by RNH1 is species specific. Using our samples, we performed a microRNA array analysis and identified microRNAs that were upregulated following a dengue virus infection, but whose expression was significantly dampened in the absence of RNH1. This suggests that RNH1 is regulating the microRNA response to virus infection, which may explain the species-specific restriction of viral replication. While more work remains to further elucidate this mechanism, the identification of RNH1 as a viral restriction factor presents a novel opportunity for therapeutic intervention to control the ever-expanding burden of dengue virus.

Updated on August 13, 2012.

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