Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus.
The immune response to influenza A virus is characterized by an influx of both macrophages and T lymphocytes into the lungs of the infected host, accompanied by induced expression of a number of CC chemokines. CC chemokine receptors CCR5 and CCR2 are both expressed on activated macrophages and T cells. We examined how the absence of these chemokine receptors would affect pulmonary chemokine expression and induced leukocyte recruitment by infecting CCR5-deficient mice and CCR2-deficient mice with a mouse-adapted strain of influenza A virus. CCR5(-/-) mice displayed increased mortality rates associated with acute, severe pneumonitis, whereas CCR2(-/-) mice were protected from the early pathological manifestations of influenza because of defective macrophage recruitment. This delay in macrophage accumulation in CCR2(-/-) mice caused a subsequent delay in T cell migration, which correlated with high pulmonary viral titers at early time points. Infected CCR5(-/-) mice and CCR2(-/-) mice both exhibited increased expression of the gene for MCP-1, the major ligand for CCR2(-/-) and a key regulator of induced macrophage migration. These studies illustrate the very different roles that CCR5 and CCR2 play in the macrophage response to influenza infection and demonstrate how defects in macrophage recruitment affect the normal development of the cell-mediated immune response.
Dawson
T C
TC
Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7525, USA.
Beck
M A
MA
Kuziel
W A
WA
Henderson
F
F
Maeda
N
N
D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology; D009980:Influenza A virus / Q000302:isolation & purification; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D011014:Pneumonia / Q000401:mortality / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000172:deficiency*; D019707:Receptors, Chemokine / Q000172:deficiency*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000502:physiology; D013997:Time Factors
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine