Natural killer cells provide protection from numerous viruses in the early stages of the infection. NK cell activity is controlled by cytokines and cell surface stimulatory and inhibitory receptors. The NKG2D stimulatory receptor has been implicated in the recognition of cells infected with viruses. NKG2D recognizes the RAET1 (including several subfamilies) and MIC families of cell surface ligands, which are poorly expressed on the surface of most normal cells. MIC and RAET1 family members are transcriptionally upregulated in cells infected with herpesviruses and most likely other viruses. Our expertise on immune recognition by NK cells (Raulet) and viral immune evasion strategies (Coscoy) will be combined to investigate our hypothesis that viral infection leads to generic signals that upregulate transcription of NKG2D ligands, but that some viruses evade recognition by preventing ligand expression at the cell surface. The long term aim of these studies is to provide routes to develop therapeutic agents that enhance NK cell responses to viruses, especially in the context of biodefense.
Our aims are to 1) focus on two herpesviruses to elucidate mechanisms that upregulate expression of NKG2D ligands in virus-infected cells, including the role of Toll like receptors, cytokines, interferons and the DNA damage pathway;2) Examine representatives of 8 virus families, including several relevant to biofense, for their capacity to upregulate NKG2D ligand mRNAs and downregulate ligand proteins;by examining a panel of mutant fibroblasts defective in a broad array of protective functions, we expect to learn the factors responsible for ligand upregulation in different viral systems;3) Determine how MHV68, a mouse gamma herpesvirus, evades NKG2D ligand upregulation, and, using two-photon microscopy, determine how NKG2D-ligand interactions impact NK cell-target cell interactions in vivo;4) Determine whether the pathways uncovered in the mouse system in aims 1-3 regulate human NKG2D ligands in human cells infected with two herpesviruses, HCMV and KSHV. Importantly, aspects of this project will be part of a collaborative effort between the different groups participating in this PO1 application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI065831-05
Application #
8113267
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$348,801
Indirect Cost
Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Chu, H Hamlet; Chan, Shiao-Wei; Gosling, John Paul et al. (2016) Continuous Effector CD8(+) T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population. Immunity 45:159-71
Han, Seong-Ji; Melichar, Heather J; Coombes, Janine L et al. (2014) Internalization and TLR-dependent type I interferon production by monocytes in response to Toxoplasma gondii. Immunol Cell Biol 92:872-81
Grover, Harshita Satija; Chu, H Hamlet; Kelly, Felice D et al. (2014) Impact of regulated secretion on antiparasitic CD8 T cell responses. Cell Rep 7:1716-1728
Young, Jennifer A; He, Tina H; Reizis, Boris et al. (2013) Commensal microbiota are required for systemic inflammation triggered by necrotic dendritic cells. Cell Rep 3:1932-44
Coombes, Janine L; Charsar, Brittany A; Han, Seong-Ji et al. (2013) Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread. Proc Natl Acad Sci U S A 110:E1913-22
Grover, Harshita Satija; Blanchard, Nicolas; Gonzalez, Federico et al. (2012) The Toxoplasma gondii peptide AS15 elicits CD4 T cells that can control parasite burden. Infect Immun 80:3279-88
Coombes, Janine L; Han, Seong-Ji; van Rooijen, Nico et al. (2012) Infection-induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus. Cell Rep 2:124-35
Dzhagalov, Ivan L; Melichar, Heather J; Ross, Jenny O et al. (2012) Two-photon imaging of the immune system. Curr Protoc Cytom Chapter 12:Unit12.26
Young, Jennifer A; Sermwittayawong, Decha; Kim, Hee-Jung et al. (2011) Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production. J Biol Chem 286:6521-31
Tam, Connie; LeDue, Jeffrey; Mun, James J et al. (2011) 3D quantitative imaging of unprocessed live tissue reveals epithelial defense against bacterial adhesion and subsequent traversal requires MyD88. PLoS One 6:e24008

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