Innate and adaptive immune responses in herpes simplex virus encephalitis

Christina Megan Kollias

doi:10.17918/00009310

Herpes simplex virus type 1 (HSV-1) is a ubiquitous, neurotropic human pathogen that causes diseases ranging from mild orofacial lesions to potentially fatal encephalitis. Cells present at the infection site express Toll-like receptors (TLRs) and intracellular nucleic acid sensors, which detect infection, produce antiviral cytokines, and limit viral invasion of the nervous system. This dissertation presents two studies examining mechanisms of resistance to HSV-1 encephalitis. In the main project, we showed TLR2-knockout (TIr2-/-) mice were highly susceptible to HSV-1-induced mortality. Their natural killer cells (NKs) responded normally, but the TIr2-/- mice exhibited impaired dendritic cell (DC) and CD8+ T cell activation. While virus replication was not different within the infected lip tissue, HSV-1 spread to the trigeminal ganglia more efficiently in the TIr2-/- group. Additionally, HSV-1 crossover to the central nervous system (CNS) was exacerbated in the deficient animals and viral loads there positively correlated with disease severity. This elevated CNS viral load precipitated the up-regulation of inducible nitric oxide synthase. Nitric oxide is neurotoxic at high concentrations and presumably its production contributed to the mortality of the TIr2 -/- group. We assessed the infiltration of leukocytes to the HSV-1-infected CNS and observed neutrophil migration to both TIr2-/- and WT brains. Lastly, we utilized an intracranial infection model to specifically assess the role of TLR2 within the CNS, but our virus proved too virulent to reveal a phenotype in the deficient mice. In the secondary project, we showed Venezuelan equine encephalitis virus replicon particles (VRPs) were effective as a prophylactic vaccine against a lethal HSV-1 challenge. Importantly, the VRP protection was non-specific, as the control GFPexpressing VRP protected as well as the HSV-1 gB-expressing VRP. Moreover, VRPs were effective for at least 4 weeks and were dependent on both NKs and DCs. Finally, we used TLR7-deficient mice to show for the first time that VRPs partially depend on this receptor for optimal protection. In summary, we utilized multiple approaches to investigate mechanisms of protection against serious HSV-1 disease. The design of efficacious anti-HSV therapies requires a full understanding of these mechanisms and this dissertation sheds light on some of these important concepts.

Innate and adaptive immune responses in herpes simplex virus encephalitis

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Innate and adaptive immune responses in herpes simplex virus encephalitis

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