Project 3 and is focused on defining immune regulatory genes and their functions that control West Nile virus (WNV) and Zika virus (ZV) infection using the Collaborative Cross (CC) mouse genetic system and human validation studies. WNV and ZV are emerging, neurotropic flaviviruses. WNV serves as a model flavivirus in mice, and we have developed novel CC mouse models of ZV infection. The CC recombinant inbred mouse panel encompasses >90% of all genetic diversity of the mouse genome and effectively models the genetic diversity found in the human population. Our Systems immunogenetics approach has identify quantitative trait loci (QTL) encoding immune-regulatory genes of WNV and ZV control. In this renewal application we will define these QTL and respective gene function in the immune regulation and control of WNV and ZV infection. Our studies of WNV infection reveal that unlike infection of inbred mice, the CC captures the full range of infection/disease outcomes found in humans, and can provide a ZV infection model in wild type CC mice. We screened 110 RI lines for WNV susceptibility and innate/adaptive immune phenotypes, from which we have linked disease and immune phenotypes to genotype. Our preliminary studies identify novel QTL encoding gene(s) linked to immune and disease phenotypes including innate and adaptive immune control of WNV and ZV susceptibility, infection in peripheral tissues, neuroinvasion, and CNS infection. Remarkably, this work reveals the Parkinson's disease gene, Park2, as an innate immune-regulatory gene that governs flavivirus infection. Our main hypothesis is that specific genes within these QTL function to control flavivirus infection and immunity. We will use our systems immunogenetics approach to investigate this hypothesis to define host genes regulating 1) innate immunity, and 2) adaptive immunity to flavivirus infection. Our study design is integrated into the larger U19 program to identify genes facilitated by the Mouse Models and System Genetics/Bioinformatics Cores. Genes we will be functionally validated in WNV and ZV infection studies, and assessed in SARS and influenza A virus studies of Projects 1 and 2) of human cells and targeted gene knockout mice to define immunoregulatory genes of virus infection.
West Nile virus and Zika virus are emerging in the USA and elsewhere. This interactive project will identify genes that control West Nile virus and Zika virus infection and immunity. The knowledge gained from this project will assist in the rational design of treatments and vaccines for protection against West Nile virus and Zika virus infection.
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| Johnson, Bryan A; Graham, Rachel L; Menachery, Vineet D (2018) Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses. Virology 517:30-37 |
| Gunn, Bronwyn M; Jones, Jennifer E; Shabman, Reed S et al. (2018) Ross River virus envelope glycans contribute to disease through activation of the host complement system. Virology 515:250-260 |
| Kollmus, Heike; Pilzner, Carolin; Leist, Sarah R et al. (2018) Of mice and men: the host response to influenza virus infection. Mamm Genome 29:446-470 |
| Gorman, Matthew J; Caine, Elizabeth A; Zaitsev, Konstantin et al. (2018) An Immunocompetent Mouse Model of Zika Virus Infection. Cell Host Microbe 23:672-685.e6 |
| Baxter, Victoria K; Heise, Mark T (2018) Genetic control of alphavirus pathogenesis. Mamm Genome 29:408-424 |
| Chow, Kwan T; Driscoll, Connor; Loo, Yueh-Ming et al. (2018) IRF5 regulates unique subset of genes in dendritic cells during West Nile virus infection. J Leukoc Biol : |
| Gralinski, Lisa E; Sheahan, Timothy P; Morrison, Thomas E et al. (2018) Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. MBio 9: |
| Menachery, Vineet D; Gralinski, Lisa E; Mitchell, Hugh D et al. (2018) Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines. J Virol 92: |
| McMullan, Rachel C; Ferris, Martin T; Bell, Timothy A et al. (2018) CC002/Unc females are mouse models of exercise-induced paradoxical fat response. Physiol Rep 6:e13716 |
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