Lack of Fas/FasL Does Not Protect from Latent Herpes Simplex 1 Infection but Decreases Virus-Induced Neurodegeneration.

Many studies have shown an association between herpes simplex virus type 1 (HSV-1) infection and the development of neurodegeneration processes later in life, such as Alzheimer's disease. The Fas/FasL death pathway plays an important role in the complex regulation of the local inflammatory response and mounting of the specific antiviral response in HSV-1 infection. Here, we applied a mouse model of latent HSV-1 neuroinfection to Fas- and FasL-deficient mice (lpr and gld) to explore whether the lack of functional Fas/FasL pathway protects from inflammation-related neurodegeneration. The latently infected Fas- and FasL-deficient mice (lpr and gld) were not protected from virus replication despite the accumulation of virus-specific cytotoxic T cells. However, the lack of Fas/FasL pathway decreased neuroinflammation- and neurodegeneration-related markers, including cognitive impairment, amyloid-β protein, and tau hyperphosphorylation. The use of a glucocorticoid, dexamethasone, to decrease neuroinflammation in wild-type mice did not protect from cognitive impairment, despite the improved antiviral response. Our data indicate that excessive neuroinflammation via the Fas/FasL pathway during HSV-1 infection is associated with neurodegeneration. Furthermore, the administration of immunomodulatory agents to ameliorate the outcome of HSV-1 latent infection should be restricted to the peak of neuroinflammation.