On the multiple role of NLRP3 on the pathogenesis of the viral infection (INM8P.444)

Herpes simplex 1 (HSV-1) infection of the eye can be a cause of blindness with lesions attributable to inflammatory events that include components of both adaptive and innate immunity. Several innate immune receptors are triggered by HSV-1 but it is unclear how such innate immune sensing relates to the subsequent control of virus and the ensuing inflammatory process. The present study focuses on the role of the inflammasome NLRP3, which is known to influence the outcome of inflammatory disease. Comparison of ocular and intradermal infection with HSV-1 in control and NLRP3 knockout mice revealed that mice lacking NLRP3 had significantly increased viral replication and delayed clearance together with increased neutrophil recruitment and proinflammatory chemokines and cytokines production compared to WT animals. Dramatic differences were also evident in the extent of skin zosteriform lesions in WT and NLRP3 KO mice. Since immunoinflammatory diseases are minimized in NLRP3 KO mice, we anticipated that SK lesions would diminish in KO mice, but instead they occurred earlier and were more severe. We demonstrate that the cellular and molecular events in SK in KO vs. WT animals were different especially in the balance of T cells type involvement and neutrophil participation. Our results indicate that NLRP3 can influence the outcome of a virus infection by affecting multiple steps in the pathogenesis.