These findings suggest that microglia activation and extracellular matrix damage may be key factors in the pathogenesis of Piry encephalitis and that an EE differentially regulates microglial activation, increases T cell infiltration, preserves the extracellular matrix, and promotes faster virus clearance from the brain. In the albino Swiss mouse model of viral encephalitis, microglial activation revealed by tomato lectin histochemistry occurred relatively early during disease progression when the first behavioral changes became apparent. Tomato lectin also binds to monocytes and B and T infiltrating lymphocytes, revealing a conspicuous accumulation of lymphocytes in virus-infected areas. In the present report, these small rounded tomato MK-2206 Akt inhibitor lectinpositive cells, morphologically distinct from ameboid microglia, accumulated in infected areas in greater concentrations in animals housed under EE conditions when compared to those housed in impoverished conditions. Of importance, no apparent difference was found between uninfected animals in EE and IE conditions in terms of the distribution of T cells in the brain parenchyma. A significant number of CD3- and some CD8- and CD43-positive cells were found in the same regions where tomato lectin-positive cells were detected. These results are compatible with previous data on VSV encephalitis. Intranasal application of VSV induces acute encephalitis characterized by a pronounced myeloid and T cell infiltration with two distinct phagocytic populations regulating VSV encephalitis but not virus clearance. VSV encephalitis is characterized by a pronounced infiltrate of myeloid cells and CD8+T cells containing a subset specific to the immunodominant VSV nuclear protein epitope. However, because ablation of peripheral macrophages does not impair VSV encephalitis or viral clearance from the brain but depletion of splenic marginal dendritic cells impairs this response and enhances morbidity/mortality, it is tempting to speculate that these dendritic cells may also be increased in EEPy as compared to IEPy animals. Another possibility is that the EE may induce NK cell activity previously described as absent in a VSV encephalitis murine model maintained in standard cages. In line with these views, voluntary exercise such as that observed in an EE increases the number of blood dendritic cells and NK cells. Because we did not use selective markers for other immune cells such as recruited monocytes/macrophages, dendritic cells, or NK cells, it remains to be confirmed whether these cells are associated or not with the immune response induced by Piry virus infection and whether or not EE PR-171 affects their distribution and number.