Phenotypic and molecular characterization of an improved model for Herpes Virus Encephalitis in humans

• Applicant: Dr. Julia Sehl-Ewert
• Subject Area: Virology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466759708

Herpes simplex virus 1 (HSV-1) is a human pathogen belonging to the alphaherpesviruses and usually causes cold sores or genital herpes, but is also one of the most commonly identified pathogens of fatal necrotizing encephalitis with a mortality rate of up to 70%. Survivors experience serious long-term effects, particularly cognitive impairment or epilepsy. To date, the pathogenesis of HSE is largely unclear.HSE primarily affects the temporal and frontal lobes of the brain. It is assumed that the virus enters the central nervous system (CNS) via the trigeminal or olfactory nerve and reaches certain brain regions due to differences in the presence of compatible receptors.After infection and replication in mucocutaneous cells, alphaherpesviruses primarily infect peripheral sensory nerves in which they are transported retrogradely to their cell bodies (e.g. trigeminal ganglion) where latent infection is established. As a result of stress, the virus can be reactivated, transported back to the periphery and shed. Latent infections were also detected in the CNS without any inflammatory response. The mechanisms that prevent or promote CNS invasion and inflammation are yet unknown.An alphaherpesvirus infection in the brain and the resulting immune response can have fatal consequences associated with massive tissue destruction. Chronic or recurring encephalitis also exist. To this day, it is unclear which factors lead to an effective and protective or a destructive immune response in HSE in the sense of an immunopathology. We recently established a new intranasal infection model in mice using a mutant of the porcine alphaherpesvirus pseudorabies virus (PrV-∆UL21/US3∆kin) showing promising analogies to human HSE, which are missing in other mouse models: i) mice developed typical meningoencephalitis in the frontal and temporal lobes, ii) mice showed behavioral disorders, and iii) some animals were completely asymptomatic despite pronounced inflammation. Based on this new system, the following questions should be answered in the project:1) What is the exact route of invasion of alphaherpesviruses into the CNS? How and why is the virus specifically transported to the temporal and frontal lobes of the brain?2) Why does alphaherpesvirus infection lead to HSE in some individuals and latency in the CNS in others without clinical disease?3) Which factors contribute to the immunopathology and thus to the long-term effects of HSE?4) What causes recurrent encephalitis?With the help of detailed characterization of our new animal model, these open questions about the pathogenesis of HSE should be answered in the future.

• DFG Programme: Research Grants
• International Connection: Denmark, United Kingdom
• Cooperation Partners: Professor Dr. John Mason; Professor Søren Riis Paludan, Ph.D.