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dc.contributor.advisorGriffin, Diane
dc.creatorDai, Wanmin
dc.date.accessioned2022-08-01T15:21:24Z
dc.date.created2022-05
dc.date.issued2022-05-05
dc.date.submittedMay 2022
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/67388
dc.description.abstractAlphaviruses are arthropod-borne viruses that can induce encephalitis in humans. Sindbis virus (SINV), a prototypic alphavirus, infects neurons and causes encephalomyelitis in mice and is a good model for studying antiviral response in the central nervous system (CNS). Mortality of mice after SINV infection is age-dependent and is influenced by neuron maturation. Interferon Regulatory Factor 7 (IRF7) is upregulated upon neuron maturation and is necessary for survival of mice after SINV infection. Among other changes, more cell death is observed in both brain and spinal cord at seven days post infection in Irf7-/- mice than in wild-type (WT) mice and this cannot be fully explained by caspase-3-dependent apoptosis. This study aims to explore the mechanism of cell death in the CNS of Irf7-/- mice. TNF-α level was higher in the CNS of Irf7-/- mice, but lack of TNF-α did not change clinical outcomes and TNF-α was not the main driver of cell death in Irf7-/- mice. I found that necroptosis executor mixed lineage kinase domain-like protein (MLKL) was significantly higher in the spinal cord of Irf7-/- mice compared to WT mice. Multiple pathways upstream of necroptosis were upregulated in the CNS of Irf7-/- mice and the upstream mediators of necroptosis in this case are not entirely clear. This thesis provides evidence that MLKL and SINV co-localized at some sites in the brain of Irf7-/- mice, indicating at least in some cells necroptosis was directly triggered by the virus infection. This process may involve RNA sensing proteins such as TLR3/TRIF or ZBP1 and is worth further exploring.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherJohns Hopkins University
dc.subjectSindbis virus
dc.subjectIRF7
dc.subjectnecroptosis
dc.subjectCNS
dc.titleREGULATION OF CELL DEATH IN THE CNS DURING SINDBIS VIRUS-INDUCED ENCEPHALOMYELITIS
dc.typeThesis
thesis.degree.disciplineImmunology
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorBloomberg School of Public Health
thesis.degree.levelMasters
thesis.degree.nameSc.M.
dc.date.updated2022-08-01T15:21:24Z
dc.type.materialtext
thesis.degree.departmentMolecular Microbiology and Immunology
local.embargo.lift2026-05-01
local.embargo.terms2026-05-01
dc.contributor.committeeMemberHardwick, Marie
dc.publisher.countryUSA


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