Modeling herpes simplex virus brain infections: Insights into human diseases

This thesis explores the pathogenesis of herpes simplex virus (HSV) and measles virus (MV) infections in the brain. HSV is the leading cause of viral encephalitis, with severe neurological consequences, while MV can persist in the brain and lead to rare but devastating complications such as subacute sclerosing panencephalitis (SSPE). Despite advances in antiviral treatments, a comprehensive understanding of how these viruses invade and persist in the brain remains incomplete. This research employs multiple experimental models—including genetically modified mice, human organotypic brain slice cultures (OBSCs), and non-human primate brain slices cultures to investigate viral neurotropism, immune responses, and neuropathological consequences. To model HSV infection, Chapter 2 describes the use of genetically modified mice to study virus-induced apoptosis in the brain, revealing that HSV triggers immune-mediated cell death through the cGAS/STING pathway, predominantly affecting microglia. Analysis of brain tissues from herpes simplex encephalitis (HSE) patients confirmed the presence of apoptotic markers, reinforcing the role of microglia in HSV neuropathogenesis. However, species-specific immune responses and structural differences in brain organization highlight the limitations of using mouse models to study human brain infections. To address these limitations, Chapter 3 explores human fetal OBSCs as a model for HSV-1 and HSV-2 infections. The results showed that HSV preferentially infects neurons and astrocytes, inducing necroptosis rather than apoptosis. Unlike in the mouse model, necroptosis was mediated by receptor-interacting protein kinases 1 and 3 (RIP1/RIP3), with a strong pro inflammatory response marked by elevated levels of TNF-α and IL-6. This suggests that OBSCs provide a more relevant model for studying early-stage HSV infections and the host response in the human brain. Building upon the potential connection between HSV and neurodegeneration, Chapter 4 investigates whether HSV contributes to Alzheimer’s disease (AD) pathology. Brain samples from HSE and AD patients, including an AD brain with concurrent HSV infection, were analyzed for amyloid-β (Aβ) and phosphorylated tau (pTau) accumulation. The findings revealed no significant increase in Aβ or pTau in HSV-infected brain regions, suggesting that acute HSV infection alone may not be a direct trigger for AD. However, the inflammatory response was heightened in HSV-infected AD brains, indicating a possible role in exacerbating neurodegenerative processes. These findings challenge the hypothesis that HSV directly drives AD pathology but leave open the possibility that chronic or recurrent HSV infections may contribute to disease progression over time. Given the challenges of studying MV neuropathogenesis in humans, Chapter 5 explores the use of non-human primate (NHP) and carnivore (dog and ferret) brain slice cultures as alternative models. The study found that MV efficiently infected neurons, oligodendrocytes, and microglia, demonstrating a neurotropism similar to that of canine distemper virus (CDV), a related morbillivirus. These results highlight the potential to utilize NHP and carnivore brain slice cultures in studying morbillivirus infections and their impact on the CNS. xiv ENGLISH SUMMARY Overall, this thesis underscores the importance of selecting appropriate experimental models to study viral brain infections. While mouse models provide valuable insights into immune mechanisms, patient samples give insights into late-stage HSV infection, human OBSCs more accurately reflect early-stage HSV infections, and NHP brain slice cultures offer a promising platform for investigating MV persistence and neurovirulence. Additionally, the findings provide new perspectives on the potential role of HSV in neurodegeneration, emphasizing the need for future research into chronic infection and inflammation-driven neurodegenerative mechanisms. Advancing human-based models and longitudinal studies will be crucial in further unraveling the complexities of viral brain infections and their long-term consequences on neurological health.