NK cells are well known for the capacity to recognize and lyse virus infected cells. Indeed, host defenses in humans and mice that lack NK cell immunity are quite vulnerable to overwhelming and recurrent Herpes virus infections. In C57BL/6 mice, host anti-murine cytomegalovirus (MCMV) immunity requires NK cell expressed Ly49H activation receptor recognition of its virus encoded m157 ligand on MCMV infected cells. We recently showed that NK cells in NZW mice however, control experimental MCMV infection without a role for Ly49H+ NK cells. Herein we have extended our finding in MA/My mice. The MA/My strain is noteworthy since it also displays very effective NK cell-mediated control of MCMV infection, but NK cells in this strain do not express Ly49H receptors. Interestingly, MCMV resistance in MA/My is strongly associated with MHC and also non MHC genes. Thus, we have found that NK cells utilize multiple antiviral control mechanisms that are distinguished by genetic polymorphism. The long-term objective of this research proposal therefore is to understand how genetic variation in host genes can contribute differently in innate immunity, its capacity to rapidly recognize and destroy viral pathogens at early times after infection and the molecular and cellular mechanisms controlling such host defenses.
The Specific Aims herein will focus initially on the identification and characterization of host genes that contribute substantially to innate anti-MCMV immunity through classical Mendelian genetics studies. The approach is based on rapid phenotypic characterization of hybrid offspring after experimental MCMV infection and subsequent genome-wide genotypic identification of each individual. Using this high-throughput genetics strategy, chromosome locations will be identified in quantitative genetics strategies, confirmed in interval-specific congenic strains, and subsequently candidate genes will be assessed in prospective molecular and biochemical analyses. To facilitate identification of host virus resistance genes, we will also investigate NK cell recognition of virus infection in cellular cytotoxicity assays and virus strain variant selection will also be used to understand innate host defenses mechanistically. While NK cells employ multiple defense mechanisms to control viral pathogens immediately after infection and before adaptive immunity is competent, our studies will no doubt have important implications for human innate defenses in CMV and potentially other virus infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050072-09
Application #
7769918
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Beisel, Christopher E
Project Start
2001-09-01
Project End
2011-03-31
Budget Start
2010-03-01
Budget End
2011-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$354,438
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Nash, William T; Gillespie, Alyssa L; Brown, Michael G (2017) Murine Cytomegalovirus Disrupts Splenic Dendritic Cell Subsets via Type I Interferon-Dependent and -Independent Mechanisms. Front Immunol 8:251
Gillespie, Alyssa; Lee, Heather; Robertson, Catherine et al. (2017) Genome-Wide Exome Analysis of Cmv5-Disparate Mouse Strains that Differ in Host Resistance to Murine Cytomegalovirus Infection. G3 (Bethesda) 7:1979-1984
Gillespie, Alyssa Lundgren; Teoh, Jeffrey; Lee, Heather et al. (2016) Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection. PLoS Pathog 12:e1005419
Teoh, Jeffrey J; Gamache, Awndre E; Gillespie, Alyssa L et al. (2016) Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation. J Immunol 197:4360-4370
Brown, Michael G; Erickson, Loren D (2015) Editorial: NK cell reaping of Tfh cells: reckless slaughter or sensible pruning? J Leukoc Biol 98:139-42
Wei, Hairong; Nash, William T; Makrigiannis, Andrew P et al. (2014) Impaired NK-cell education diminishes resistance to murine CMV infection. Eur J Immunol 44:3273-82
Nash, William T; Teoh, Jeffrey; Wei, Hairong et al. (2014) Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control. Front Immunol 5:175
Prince, Jessica; Lundgren, Alyssa; Stadnisky, Michael D et al. (2013) Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control. J Immunol 191:4709-19
Ge, Yan; Brown, Michael G; Wang, Hongyang et al. (2012) Genetic approach to study lupus glomerulonephritis. Methods Mol Biol 900:271-90
Carroll, Virginia A; Lundgren, Alyssa; Wei, Hairong et al. (2012) Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease. J Virol 86:2132-42

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