The overall objective of the proposed studies is to gain significant insight into how the body's innate immune system responds to virus infections. This work is important because the innate immune system responds very early during infection and alerts other host defense components. Natural killer (NK) cells are best known for killing tumor cells but they have an important role in innate immunity against pathogens, such as cytomegalovirus (CMV), a major cause of morbidity and mortality, especially in immunocompromised human patients. In order to study NK cell responses to viruses, the applicant's laboratory has chosen to study murine CMV (MCMV) because CMV has species tropism. Nevertheless, MCMV recapitulates most features of human CMV infections, making it an important animal model. In prior work, the applicant's laboratory and collaborators identified Ly49H, an NK cell activation receptor, as responsible for genetic resistance to MCMV infection. In the previous funding period, the applicant's laboratory discovered that Ly49H specifically recognizes an MCMV-encoded molecule, termed m157, that appears to be structurally related to other putative, virus-encoded MHC class l-like molecules that may be involved in immune modulation. m157 expression triggers Ly49H-dependent target killing and cytokine production. In the genetic absence of Ly49h, anti-Ly49H treatment, or deletion of m157, infection is uncontrolled and early lethality ensues. However, in immunodeficient mice, m157 mutant viruses emerge, resulting in lethality at much later times, and indicating selection pressure from NK cells. However, some escape mutants have intact m157, suggesting they are escaping other innate immune components. In preliminary studies, the applicant's laboratory discovered that MCMV-infected cells appear early in the marginal zone of the spleen and have an unusual morphology. In addition, the investigators have produced new mice constitutively expressing a ligand for an NK cell activation receptor. These mice will be useful study NK cell tolerance.
The specific aims of this renewal application are thus to study: 1) The interaction of NK cells with MCMV-infected cells in vivo;2) Immune modulation by MCMV;and 3) NK cell function in host expressing a ligand for an activation receptor. Therefore, these studies will provide significant insight into the molecular basis for host anti-viral defense in innate immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Beisel, Christopher E
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
Parikh, Bijal A; Piersma, Sytse J; Pak-Wittel, Melissa A et al. (2015) Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells. PLoS Pathog 11:e1005323
Chapa, Travis J; Johnson, L Steven; Affolter, Christopher et al. (2013) Murine cytomegalovirus protein pM79 is a key regulator for viral late transcription. J Virol 87:9135-47
Fogel, Leslie A; Yokoyama, Wayne M; French, Anthony R (2013) Natural killer cells in human autoimmune disorders. Arthritis Res Ther 15:216
Elliott, Julie M; Yokoyama, Wayne M (2011) Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol 32:364-72
Vivier, Eric; Raulet, David H; Moretta, Alessandro et al. (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44-9
Cooper, Megan A; Yokoyama, Wayne M (2010) Memory-like responses of natural killer cells. Immunol Rev 235:297-305
Higuchi, D A; Cahan, P; Gao, J et al. (2010) Structural variation of the mouse natural killer gene complex. Genes Immun 11:637-48
Cheng, Tammy P; Valentine, Mark C; Gao, Jian et al. (2010) Stability of murine cytomegalovirus genome after in vitro and in vivo passage. J Virol 84:2623-8
Cooper, Megan A; Colonna, Marco; Yokoyama, Wayne M (2009) Hidden talents of natural killers: NK cells in innate and adaptive immunity. EMBO Rep 10:1103-10
Cooper, Megan A; Elliott, Julie M; Keyel, Peter A et al. (2009) Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A 106:1915-9

Showing the most recent 10 out of 15 publications