Viral respiratory infections cause significant disease and mortality in humans and can exacerbate pre-existing conditions such as asthma. Although certain aspects of viral pathogenesis have been studied extensively, mechanisms regulating leukocyte trafficking during the immune response to viral infection are poorly understood. Chemokines are a superfamily of structurally- related cytokines and are thought to play key roles in leukocyte trafficking.
The aim of this study is to elucidate the role of chemokines and their receptors in the immune response to murine gammaherpesvirus 68 (MHV-68). Mice infected with MHV-68 develop an acute respiratory disease similar to influenza. MHV-68 also induces lymph node enlargement, splenomegaly, and mononucleosis in mice, as Epstein Barr virus does in humans. Interestingly, the MHV-68 genome encodes a CXCR2 chemokine receptor homologue which may play a role in viral pathogenesis. This viral chemokine receptor is conserved in closely-related gammaherpesviruses such as human herpesvirus 8 (HHV8) which has been implicated in the development of Kaposi's sarcoma and certain types of lymphoma. Studying NMV-68 infection in mice, may provide insight into the role of chemokines and their receptors in human disease caused by viruses. This work may have important implications for therapeutic intervention through the enhancement or inhibition of chemokine expression. In the proposed study: 1) The role of MIP-1alpha, MCP-1, CCR2 and CXCR2 in the immune response to MHV-68 will be examined by using mice deficient in, or overexpressing these genes, while the role of lymphotactin, Crg-2, RANTES, and MIP-1beta will be determined using neutralizing antisera to these factors. 2) The effect of pre-existing allergic inflammation on the immune response to MHV- 68, viral pathogenesis and the chemokine profile will be determined. The role of specific chemokines will be studied by using mice lacking these chemokines or their receptors or by using neutralizing antibodies. 3) The role of the CXCR2 chemokine receptor homologue in viral pathogenesis will be determined using a mutant virus in which the gene encoding the CXCR2 homologue has been inactivated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI044247-01A1
Application #
2902175
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Ash-Shaheed, Belinda
Project Start
1999-09-01
Project End
2003-07-31
Budget Start
1999-09-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wareing, Mark D; Shea, Ashley L; Inglis, Chandra A et al. (2007) CXCR2 is required for neutrophil recruitment to the lung during influenza virus infection, but is not essential for viral clearance. Viral Immunol 20:369-78
Wareing, Mark D; Lyon, Ashley; Inglis, Chandra et al. (2007) Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2-/- mice. J Leukoc Biol 81:793-801
Lee, Bong Joo; Giannoni, Francesca; Lyon, Ashley et al. (2005) Role of CXCR3 in the immune response to murine gammaherpesvirus 68. J Virol 79:9351-5
Wareing, Mark D; Lyon, Ashley B; Lu, Bao et al. (2004) Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J Leukoc Biol 76:886-95
Sarawar, Sally R; Lee, Bong Joo; Giannoni, Francesca (2004) Cytokines and costimulatory molecules in the immune response to murine gammaherpesvirus-68. Viral Immunol 17:3-11
Lee, Bong Joo; Koszinowski, Ulrich H; Sarawar, Sally R et al. (2003) A gammaherpesvirus G protein-coupled receptor homologue is required for increased viral replication in response to chemokines and efficient reactivation from latency. J Immunol 170:243-51
Lee, Bong Joo; Reiter, Su Khoh; Anderson, Mandy et al. (2002) CD28(-/-) mice show defects in cellular and humoral immunity but are able to control infection with murine gammaherpesvirus 68. J Virol 76:3049-53
Sarawar, S R; Lee, B J; Reiter, S K et al. (2001) Stimulation via CD40 can substitute for CD4 T cell function in preventing reactivation of a latent herpesvirus. Proc Natl Acad Sci U S A 98:6325-9
Lee, B J; Santee, S; Von Gesjen, S et al. (2000) Lymphotoxin-alpha-deficient mice can clear a productive infection with murine gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J Virol 74:2786-92