Neuronal nitric oxide synthase: a possible inflammatory mediator responsible for host-induced susceptibility to herpes simplex encephalitis (VIR9P.1153)

Abstract

Abstract Herpes Simplex Virus Type-1 (HSV-1) infection can result in a severe disease of the central nervous system termed Herpes Simplex Encephalitis (HSE). In both animals and humans, the immune response is known to play a role in HSE progression. Using resistant and susceptible HSE mouse models, we have characterized late-stage (>day 7 post-infection (p.i.)) inflammation by which susceptible mice succumb to HSE. Previous data have indicated that immune dysregulation between the two strains is evident at day 6 p.i. Thus, we propose that activation of specific pathways before day 6 p.i. result in an inflammatory cascade that contributes to HSE. To demonstrate this, resistant C57BL/6 and susceptible 129S6 male mice were infected with HSV-1 and brainstems were collected days 1-4 p.i. Microarrays, Ingenuity Pathway Analysis (IPA), and QRT-PCR were performed on RNA, and protein levels were determined via westerns. IPA predicated several inflammatory functions, such as migration of immune cells, to be 129S6-biased (p<0.05). Among the dysregulated transcripts identified by the microarray, neuronal nitric oxide synthase (nNOS) was shown to be significantly upregulated in susceptible 129S6 mice on day 3 p.i at both the RNA (p<0.01) and protein level (p<0.001). Our results implicate nNOS as a regulator of HSE pathogenesis and we are currently performing animal studies to better define the role of nNOS in HSE progression.