Evidence for differential roles for NKG2D receptor signaling in innate host defense against coronavirus-induced neurological and liver disease.
Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-gamma) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-gamma production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-gamma expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-gamma and tumor necrosis factor alpha secretion.
Walsh
Kevin B
KB
Department of Molecular Biology & Biochemistry, 3205 McGaugh Hall, University of California, Irvine, Irvine, CA 92697-3900, USA.
Lodoen
Melissa B
MB
Edwards
Robert A
RA
Lanier
Lewis L
LL
Lane
Thomas E
TE
D000818:Animals; D001927:Brain Diseases / Q000276:immunology* / Q000821:virology; D003333:Coronaviridae Infections / Q000276:immunology*; D017934:Coronavirus / Q000276:immunology / Q000302:isolation & purification*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008107:Liver Diseases / Q000276:immunology* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction
C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma