Chemokine receptor Ccr2 is critical for monocyte accumulation and survival in West Nile virus encephalitis.
West Nile virus (WNV) is a re-emerging pathogen responsible for outbreaks of fatal meningoencephalitis in humans. Previous studies have suggested a protective role for monocytes in a mouse model of WNV infection, but the molecular mechanisms have remained unclear. In this study, we show that genetic deficiency in Ccr2, a chemokine receptor on Ly6c(hi) inflammatory monocytes and other leukocyte subtypes, markedly increases mortality due to WNV encephalitis in C57BL/6 mice; this was associated with a large and selective reduction of Ly6c(hi) monocyte accumulation in the brain. WNV infection in Ccr2(+/+) mice induced a strong and highly selective monocytosis in peripheral blood that was absent in Ccr2(-/-) mice, which in contrast showed sustained monocytopenia. When a 1:1 mixture of Ccr2(+/+) and Ccr2(-/-) donor monocytes was transferred by vein into WNV-infected Ccr2(-/-) recipient mice, monocyte accumulation in the CNS was not skewed toward either component of the mixture, indicating that Ccr2 is not required for trafficking of monocytes from blood to brain. We conclude that Ccr2 mediates highly selective peripheral blood monocytosis during WNV infection of mice and that this is critical for accumulation of monocytes in the brain.
Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Jean K
JK
Lim
Christopher J
CJ
Obara
Aymeric
A
Rivollier
Alexander G
AG
Pletnev
Brian L
BL
Kelsall
Philip M
PM
Murphy
D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D006801:Humans; D007964:Leukocytosis / Q000276:immunology / Q000473:pathology / Q000821:virology; D007970:Leukopenia / Q000276:immunology / Q000473:pathology / Q000821:virology; D008024:Ligands; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014709:Vero Cells; D019562:Viral Load / Q000235:genetics / Q000276:immunology; D014901:West Nile Fever / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D014902:West Nile virus / Q000276:immunology*
C515335:Ccr2 protein, mouse; D008024:Ligands; D054390:Receptors, CCR2