CXCR3-deficiency protects influenza-infected CCR5-deficient mice from mortality

Abstract

Mice lacking the chemokine receptor CCR5 are susceptible to mortality from a normally non-lethal influenza infection. Here we found that CXCR3-deficiency rescued CCR5-deficient (CCR5-/-) mice from influenza-induced mortality. The number of mononuclear phagocytes in the airways was transiently increased in CCR5-/- mice but not in CXCR3-CCR5 double-deficient mice. Antigen-specific CXCR3-CCR5 double-deficient CD8 effector cells were less efficient at entering the airways compared with WT or CCR5-/- CD8 effector cells. The decrease in inflammatory cell infiltrates in CXCR3-CCR5 double-deficient-infected mice correlated with a decrease in CCL2 and IFN-γ production in the airways. Finally, CXCR3-CCR5 double-deficient mice that survived the primary viral challenge were protected from a lethal secondary challenge, indicating that T-cell-mediated protective memory was not compromised in mice lacking these chemokine receptors. In conclusion, CXCR3-deficiency attenuated the lethal cellular immune response in CCR5-/- influenza-infected mice without hindering viral clearance or long-term immunity. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.