Toll-like receptor 2 is required for complete protection against lethal HSV-1 encephalitis in a murine lip scarification model (168.25)

Abstract

Abstract Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen capable of causing fatal encephalitis in rare instances. The immediate recognition of the virus by pattern recognition receptors at the infection site is crucial for establishing an antiviral state and limiting nervous system involvement. The importance of TLR3 and TLR9 in the type I interferon-dependent protection against HSV disease has been well documented, however, the role of TLR2 is less clear. This study aims to define the function of TLR2 in a natural infection model of mucocutaneous HSV-1 disease. TLR2 is expressed on the cell surface of various cell types, and ligation leads to an NF-B-dependent inflammatory response. Here we demonstrate that Tlr2-/- mice are significantly more susceptible to HSV-1 disease than WT controls. Whereas Tlr2-/- mice have indistinguishable levels of infectious virus at the inoculation site, the deficient animals display faster nervous system invasion and elevated viral loads in the trigeminal ganglia, brainstem, and brain, indicating that TLR2-expressing cells in the nervous system aid in controlling HSV-1 replication and spread. Mortality from HSV-1 CNS infection is the result of virus-mediated cytotoxicity in combination with the ensuing neuroinflammatory response. We are currently assessing the magnitude and kinetics of CNS inflammation as well as the activation and infiltration of immune cells to the CNS in order to delineate the mechanism of TLR2 protection.