Larissa B. Thackray, PhD
Associate Professor of Medicine
Members of the flavivirus genus, many of which are characterized as NIAID Emerging Infectious Disease Pathogens, include West Nile (WNV), Dengue (DENV), and Zika viruses. Flaviviruses account for approximately 400 million infections per year, with billions at risk and no specific therapies available to date. While the majority of flavivirus infections in humans are subclinical, a subset of individuals develops severe disease. Patient age, underlying immune status, and genetic polymorphisms are associated with increased susceptibility for WNV and DENV, however these risk factors do not account for most adverse outcomes. Moreover, the contribution of environmental factors to flavivirus disease severity remains ill-defined.
Previous studies have defined complex interactions between the mammalian gut microbiota, host immunity, and virus infection in which the microbiota influences host resistance to some viruses, yet also promotes infection of others. Using mouse models of flavivirus infection, we have recently demonstrated that antibiotic treatment that depletes and perturbs the gut microbiota impairs host immunity and increases susceptibility to severe flavivirus infections. Consequently, an expanded understanding of interactions between the mammalian microbiota, host immunity, and the outcome of systemic virus infection is essential for developing novel strategies to ameliorate human disease.
Thackray LB, Handley SA, Gorman MJ, Poddar S, Bagadia P, Briseño CG, Theisen DJ, Tan Q, Hykes BL Jr., Lin H, Lucas TM, Desai C, Gordon JI, Murphy KM, Virgin HW, Diamond MS. Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections. Cell Rep. 2018 Mar 27;22(13):3440-3453.e6. doi: 10.1016/j.celrep.2018.03.001. PMID: 29590614
Handley SA, Thackray LB, Zhao G, Presti R, Miller AD, Droit L, Abbink P, Maxfield LF, Kambal A, Duan E, Stanley K, Kramer J, Macri SC, Permar SR, Schmitz JE, Mansfield K, Brenchley JM, Veazey RS, Stappenbeck TS, Wang D, Barouch DH, Virgin HW. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell. 2012 Oct 12;151(2):253-66. doi: 10.1016/j.cell.2012.09.024. PMID: 23063120
Hwang S, Maloney NS, Bruinsma MW, Goel G, Duan E, Zhang L, Shrestha B, Diamond MS, Dani A, Sosnovtsev SV, Green KY, Lopez-Otin C, Xavier RJ, Thackray LB, Virgin HW. Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. Cell Host Microbe. 2012 Apr 19;11(4):397-409. doi: 10.1016/j.chom.2012.03.002. PMID: 22520467