The role played by resident microglia and by the infiltration of peripheral monocytes/macrophages in the innate immune response during herpes simplex virus type 1 (HSV-1) encephalitis was evaluated in mice deficient for the CCR2 and CX3CR1 receptors. CCR2(-/-), CX3CR1(-/-) and C57BL/6 wild-type (WT) male mice were infected intranasally with 7×10(5) p.f.u. of an HSV-1 clinical strain and monitored for signs of encephalitis and survival. In addition, brain viral DNA load and cytokine levels were evaluated by RT-PCR and magnetic bead-based immunoassay, respectively. The cellular response was assessed by fluorescence-activated cell sorting of blood and brain leukocytes. Infected CX3CR1(-/-) mice had a significantly lower mean life expectancy than WT mice (P<0.05, log-rank test) and demonstrated an increased infiltration of Ly-6C(high) 'inflammatory' macrophages in the brain (P<0.05). Infected CCR2(-/-) mice had fewer monocytes (P<0.05), with a lower proportion of Ly-6C(high) 'inflammatory' monocytes in the blood than the other groups (P<0.05). Brain viral DNA loads were only slightly higher in knockout mice than in WT mice (P-value not significant). These data suggest that CCR2 and especially CX3CR1 receptors are necessary to initiate a proper immune response during HSV encephalitis. More precisely, CCR2 is crucial for the emigration of monocytes from the bone marrow to the blood, whereas CX3CR1 is mostly implicated in the regulation of infiltrating cells from the blood to the site of infection and in the control of the immune homeostasis of the brain.