Natural killer (NK) cells are essential immune effector cells due to their intrinsic capacity to detect and destroy virus-infected and malignant target cells. In control of this essential function is an array of highly polymorphic cell surface receptors that regulate NK cell effector functionality. Human genetics studies have shown that certain combined gene sets for killer immunoglobulin-related receptor (KIR) NK-cell receptors and their HLA class I ligands affect clinical outcomes in autoimmunity, infection, transplantation and pregnancy syndromes. However, the molecular and cellular bases of these effects are not understood. Our prior mouse genetics studies have also found that significant genetic interaction between gene sets for NK receptors and MHC class I ligands controls NK cell features, and possibly their capacity to mediate critical antiviral functions and protection from immune- or virus-mediated tissue damage and disease. A MHC-linked quantitative trait locus (QTL), Cmv5, that specifically regulates NK cells, secondary lymphoid organ (SLO) structures, and tissue necrosis in spleen after viral infection was also recently discovered. However, it is not known how Cmv5 traits are regulated, how distinct alleles affect histopathological outcomes, or if genetic control manifests through hematopoietic cells, non-hematopoietic cells, or both. We hypothesize that Cmv5 regulation of NK cells and lymphoid architecture during acute virus infection can profoundly impact the tempo/extent of viral clearance and tissue inflammation. Likewise, Cmv5 may affect priming of adaptive immunity, memory formation and ultimate disease outcomes. The broad long-term objectives of this research proposal, therefore, center on identifying and fully characterizing MHC I Dk, NKC and Cmv5 genetic modifiers to elucidate how genetic variation controls NK cells, SLO structures and tissue necrosis in infected tissues following acute viral infection. To achieve the objectives, Aim 1 investigates molecular and cellular bases of Cmv5s suppression of NK expansion and SLO structure protection during inflammation and pathogen infection. Classical genetics and genetic screens will be applied to precisely map a Cmv5 critical interval. Exome sequence variant analyses, and chromosome editing strategies will be applied to further minimize the interval by constructing Cmv5 interval/candidate sequence deletions and testing for loss of suppression mutations in experimental cross mice.
Aim 2 explores the NKC effect on Cmv5 regulation of NK expansion and SLO protection in MCMV- infected spleen. We hypothesize that strain-specific regulation of Cmv5 effects is controlled at the level of NK cell effector functionality, and reactivity to viral infection. NKC variation, resulting in NK receptor diversity, will be carefully assessed for its effect on Cmv5 regulation of NK cells, SLO structural integrity and tissue necrosis during viral infection in congenic, transplanted and NK receptor gene-edited mouse strains. Our studies should ascertain how NKC and MHC genetic interaction specifically shapes NK cells, additional critical immune cells, and inflammatory responses, which may help to model combined KIR/HLA associations with clinical response.

Public Health Relevance

. One quarter of the human population worldwide is expected to perish due to infectious causes. Natural killer (NK) cells are essential in human health due to their innate ability to swiftly detect and destroy virus-infected and malignant cells. This research proposal aims to discover and characterize genetic factors that mediate critical regulation of NK cells, tissue inflammation, lymphoid organ structures and disease features during viral infection, which is also relevant to understanding how genetic control of innate immune features influences the priming and development of highly specific adaptive immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050072-18
Application #
9852985
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Beisel, Christopher E
Project Start
2001-09-01
Project End
2022-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
18
Fiscal Year
2020
Total Cost
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
Shi, Lei; Li, Kang; Guo, Yizhan et al. (2018) Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. Proc Natl Acad Sci U S A 115:11808-11813
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
Krueger, Peter D; Narayanan, Sowmya; Surette, Fionna A et al. (2017) Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells. J Leukoc Biol 101:329-338
Nash, William T; Gillespie, Alyssa L; Brown, Michael G (2017) Murine Cytomegalovirus Disrupts Splenic Dendritic Cell SubsetsviaType I Interferon-Dependent and -Independent Mechanisms. Front Immunol 8:251
Brown, Michael G; Gamache, Awndre (2017) Editorial: On matters of maturity, self-control, and responsiveness: inhibitory NK receptors in the driver's seat? J Leukoc Biol 102:1281-1284
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

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