Determinants of Host Outcome of Sindbis Virus-Induced Encephalomyelitis
TROISI-DISSERTATION-2020.pdf (20.47Mb) (embargoed until: 2022-05-01)
Troisi, Elizabeth M
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Encephalitic arthropod-borne viruses including alphaviruses are significant causes of morbidity worldwide. The alphavirus Sindbis virus (SINV), infects neurons in mice and causes encephalomyelitis, serving as a model for understanding mechanisms required to control viral infection within the central nervous system (CNS). Outcome of neurotropic SINV infection in mice is dependent on factors including age, type I interferon (IFN), and anti-SINV antibody. The goal of this work is to further define these factors. The first part defines the mechanism by which different inoculation routes lead to varied outcome following SINV infection. While deaths are rare in C57BL/6 mice following intracranial infection with a relatively avirulent strain, 20-30% die following intranasal infection. To understand this difference, we compared the immune responses between the mice that die and those that survive infection. Widespread distribution of infection and delayed viral clearance were associated with lower levels of antibody in the brain compared to recovering mice, further showing the importance of antibody in controlling viral infection within the CNS. The second part evaluates the roles of IFN regulatory factors (IRFs) 3 and 7 following SINV infection, two transcription factors important for type I IFN induction. SINV-infected Wild-type (WT) and Irf3-/- mice developed mild encephalomyelitis and recovered, while Irf7-/- mice became paralyzed and died, which was not due to lack of a type I IFN response in the CNS. Irf7-/- mice were unable to clear virus from the brain and had SINV infection in the brainstem at the time of severe disease and mortality. SINV infection in Irf7 deficient mature neurons was associated with accelerated virus replication, demonstrating that IRF7 could be required to control viral replication and prevent fatal disease in neurotropic SINV infection. The last part evaluates the roles of IRF3 and IRF7 in the antiviral immune response to neurotropic SINV infection. Deficiency in each of these transcription factors was associated with enhanced immunopathology and cytokine production. However, IRF7 deficiency was associated with enhanced cell death throughout the CNS that may be exacerbated by TNF alpha, further defining the requirement of IRF7 for survival from SINV-induced encephalomyelitis through its regulation of the inflammatory response.