West Nile virus (WNV) is a neurotropic virus well documented to require innate immunity, humoral immunity, as well as T-cell mediated immunity in order to generate effective protection and viral control. Due to the varied and complex nature of the immune responses generated in response to WNV infection, there are naturally complex and varied genetic networks involved in immunity to WNV as well, though to date, we lack a complete understanding of how host genetic diversity impacts the orchestration of immunity to virus infection. Thus, the goal of Project 4 is to use a systems immunology approach to identify candidate host genes and genetic networks that control regulation of adaptive immunity, as well as the interplay between innate and adaptive immunity, to West Nile virus infection, thereby providing us with a better understanding of how adaptive immunity to neurotropic viruses is regulated at the genetic level. In order to accomplish this goal, we plan to use the Collaborative Cross (CC) mice, a highly diverse recombinant inbred mouse panel designed to promote the identification and characterization of multiple interacting genes underlying complex phenotypes, such as host immunity to viral infection. The use of this unique genetic tool will therefore allow us to identify multiple immunoregulatory genes and genetic networks that control various aspects of WNV induced adaptive immunity, and in conjunction with Project 3, the goal of which is to identify genes regulating innate immunity to WNV, to link innate and adaptive immune networks in response to WNV. This will ultimately allow us to not only validate these targets in human systems, but also to generate more effective animal models of virus infection so that we can better simulate human diversity and make further discoveries that will allow us to create better vaccines and therapies for West Nile and other neuroinvasive viral diseases.

Public Health Relevance

Through the findings of this interactive program, we will significantly advance our understanding of how genes and genetic networks regulate the adaptive immune response to virus infection, both globally as well as specifically in the case of neuroinvasive infections. This will likely lead to improved treatment and therapeutics for various clinically important infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100625-03
Application #
8706024
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
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
Menachery, Vineet D; Schäfer, Alexandra; Burnum-Johnson, Kristin E et al. (2018) MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape. Proc Natl Acad Sci U S A 115:E1012-E1021
Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374

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