Members of Flavivirus genus are the most important arthropod-borne viruses causing disease in humans. This genus includes viruses (West Nile virus (WNV), Japanese encephalitis virus (JEV) and Dengue virus (DENV)) that are re-emerging and becoming endemic in new areas of the world. Flaviviruses account for ~100 millions infections per year, with billions at risk and no specific therapy available. Although interferon (IFN) responses control the cell and tissue tropism of WNV and other flaviviruses, the specific effector molecules that restrict infection remain poorly characterized. The studies in this collaborative and inter-disciplinary project between the Diamond and Chanda laboratories will use genetic screens to identify novel interferon stimulated genes (ISG) that modulate flavivirus infection in specific cell types ex vivo and in vivo. Loss-of-function high-throughput genetic screens will be performed with a custom- generated GFP-marked shRNA library targeting ~700 mouse and human ISGs, to identify novel ISG that restrict infection of virulent and attenuated strains of WNV. Using stable cell lines that have targeted reductions or ectopic expression of candidate ISGs, we will define mechanistically how novel ISG effector molecules restrict specific steps in the viral lifecycle and influence infection outcome. In preliminary studies, we have identified several candidate inhibitory ISG (Ifi27, IFIT2, and IFITM3) that attenuate WNV infection, and already acquired or generated knockout mice. Using these mice, we will evaluate the function of these particular ISGs in restricting WNV replication in a cell-specific manner and in vivo. We hypothesize that specific ISGs have antiviral properties that differentially control WNV infection and spread, and that these demonstrate tissue and cell-type specificity. Overall, these experiments will more clearly define the interface between IFN control and flavivirus pathogenesis and possibly, guide strategies that modulate immunity to infection by this family of viruses.

Public Health Relevance

The continual outbreaks of flavivirus disease highlight a need for an expanded understanding of mechanisms of immune control. Insight into the cell-intrinsic immune processes that restrict flavivirus infection is essential for developing novel strategies to contain disease. These experiments will define the interface between IFN control and flavivirus pathogenesis and guide strategies that modulate immunity to infection by positive strand RNA viruses of global concern.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Virology - B Study Section (VIRB)
Program Officer
Singleton, Kentner L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Fernandez, Estefania; Diamond, Michael S (2017) Vaccination strategies against Zika virus. Curr Opin Virol 23:59-67
Cao, Bin; Parnell, Lindsay A; Diamond, Michael S et al. (2017) Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice. J Exp Med 214:2303-2313
Morrison, Thomas E; Diamond, Michael S (2017) Animal Models of Zika Virus Infection, Pathogenesis, and Immunity. J Virol 91:
Shan, Chao; Muruato, Antonio E; Jagger, Brett W et al. (2017) A single-dose live-attenuated vaccine prevents Zika virus pregnancy transmission and testis damage. Nat Commun 8:676
Wen, Jinsheng; Elong Ngono, Annie; Regla-Nava, Jose Angel et al. (2017) Dengue virus-reactive CD8+ T cells mediate cross-protection against subsequent Zika virus challenge. Nat Commun 8:1459
Hastings, Andrew K; Yockey, Laura J; Jagger, Brett W et al. (2017) TAM Receptors Are Not Required for Zika Virus Infection in Mice. Cell Rep 19:558-568
Richner, Justin M; Jagger, Brett W; Shan, Chao et al. (2017) Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. Cell 170:273-283.e12
Miner, Jonathan J; Diamond, Michael S (2017) Zika Virus Pathogenesis and Tissue Tropism. Cell Host Microbe 21:134-142
Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D et al. (2017) Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 214:2843-2857
Jagger, Brett W; Miner, Jonathan J; Cao, Bin et al. (2017) Gestational Stage and IFN-? Signaling Regulate ZIKV Infection In Utero. Cell Host Microbe 22:366-376.e3

Showing the most recent 10 out of 43 publications