NK cells have been shown to be important in defense against tumors and infections. The overall goal of this study is to characterize key molecular events controlled by innate cytokines and chemokines for promoting the recruitment of NK cells for delivery of antiviral defense and downstream T cell responses to liver. A protective role for NK cells and NK cell-derived IFN-gamma during MCMV infection has been clearly established. During MCMV infections of mice the chemokine MIP-1alpha/CCL3 promotes NK cell migration and delivery of IFN-gamma at tissues sites of viral infection to mediate downstream protective responses. Recently, type 1 interferons (IFN-alpha/beta) were identified as key initiators of the MIP-1alpha production that is necessary for NK cell inflammation and innate protection against MCMV. These studies defined a cellular delivery mechanism by which innate cytokines promote local immune responses. Experiments planned here will provide new insights into the intrinsic cytokine-chemokine networks that regulate localized recruitment of innate effector cells for antiviral defense, as well as characterize the cytokine-chemokine functions that shape adaptive immune responses. The focal hypotheses are that (i) IFNalpha/beta-mediated recruitment of MIP-l?-producing cells in liver during MCMV infection occurs as a result of the following steps: 1) infection in liver induces the release of IFN-alpha/beta from uninfected or infected macrophage populations, Kupffer cells, and/or dendritic cell subsets, 2) to induce production of intermediary chemokines, e.g. MCP-1/CCL2, and/or chemokine receptors, e.g. CCR2, 3) to promote NK cell trafficking and innate antiviral defense; and (ii) NK cell inflammatory responses help shape adaptive immunity by: 1) inducing production of IFNgamma-inducible chemokines, 2) that mediate recruitment of T lymphocytes during late MCMV infection in liver. These will be examined by asking the following questions in 3 Specific AIMS. 1) What cell types are induced to produce IFN-alpha/beta during virus infection and what are the contributions of virus to cytokine production in liver? 2) What are the chemokines and chemokine producers, as well as the target cells, activated or responding to IFN-alpha/beta 3) Are gamma-inducible chemokines mediating downstream T cell responses in liver? Molecular, histological, immunological, and cell trafficking studies will be used to answer these questions. The experiments will take advantage of mice genetically deficient in chemokine or chemokine receptors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102708-02
Application #
6796827
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2003-09-01
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$253,376
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Crane, Meredith J; Gaddi, Pamela J; Salazar-Mather, Thais P (2012) UNC93B1 mediates innate inflammation and antiviral defense in the liver during acute murine cytomegalovirus infection. PLoS One 7:e39161
Crane, Meredith J; Hokeness-Antonelli, Kirsten L; Salazar-Mather, Thais P (2009) Regulation of inflammatory monocyte/macrophage recruitment from the bone marrow during murine cytomegalovirus infection: role for type I interferons in localized induction of CCR2 ligands. J Immunol 183:2810-7
Hokeness-Antonelli, Kirsten L; Crane, Meredith J; Dragoi, Ana M et al. (2007) IFN-alphabeta-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection. J Immunol 179:6176-83
Hokeness, Kirsten L; Deweerd, Elizabeth S; Munks, Michael W et al. (2007) CXCR3-dependent recruitment of antigen-specific T lymphocytes to the liver during murine cytomegalovirus infection. J Virol 81:1241-50
Salazar-Mather, T P; Hokeness, K L (2006) Cytokine and chemokine networks: pathways to antiviral defense. Curr Top Microbiol Immunol 303:29-46
Hokeness, Kirsten L; Kuziel, William A; Biron, Christine A et al. (2005) Monocyte chemoattractant protein-1 and CCR2 interactions are required for IFN-alpha/beta-induced inflammatory responses and antiviral defense in liver. J Immunol 174:1549-56