A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense.
Macrophage inflammatory protein 1alpha (MIP-1alpha) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell-produced interferon gamma (IFN-gamma) contributes to defense against MCMV infections. A specific role for local NK cell IFN-gamma production, however, has not been established. The importance of MIP-1alpha and NK cell-produced IFN-gamma in shaping endogenous immune responses and defense in different compartments was examined. MIP-1alpha deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-gamma production in liver. MIP-1alpha-independent IFN-gamma responses were observed in serum and spleen, and infection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak liver expression of another chemokine, the monokine induced by IFN-gamma (Mig), depended upon presence of MIP-1alpha, NK cells, and IFN-gamma. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1alpha is critical for NK cell migration and IFN-gamma delivery to mediate protection; and Mig induction in tissues is a downstream protective response resulting from the process. These results define a critical chemokine-to-cytokine-to-chemokine cascade required for defense during a viral infection establishing itself in tissues.
Salazar-Mather
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Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
Hamilton
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Biron
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D000818:Animals; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008099:Liver / Q000276:immunology / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D018146:Muromegalovirus / Q000276:immunology*; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology
D000941:Antigens; D000954:Antigens, Surface; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D037181:Lectins, C-Type; D019402:Macrophage Inflammatory Proteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D007371:Interferon-gamma