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Rift Valley fever virus (RVFV), an arbovirus with epidemic potential, can manifest as late-onset encephalitis in humans, yet this disease outcome remains understudied. A lethal rodent model of RVF encephalitis is characterized by a dysregulated immune response, neuronal necrosis, and blood-brain barrier breakdown that precedes lethality. In this study, we built upon this prior work using both\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      models to interrogate the mechanism of cell death in neurons during RVFV infection. We found an increase in proteins associated with apoptosis, pyroptosis, and necroptosis in the brains of animals that succumb to lethal RVFV encephalitis. We then focused on identifying the primary cell death pathways in primary cortical neurons, which were highly susceptible to infection by pathogenic and attenuated viral strains. Using immunoblotting, immunocytochemistry, and in-cell western assays, we found that neurons infected with RVFV resulted in the activation of multiple cell death pathways, leading to neuron cell death. These findings further our understanding of the impact of RVFV infection, which is critical to identifying therapeutics that support neuron integrity and minimize injury during viral encephalitis.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Rift Valley fever may be accompanied by late-onset encephalitis in humans. Our lab has studied the\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        mechanisms of neurological disease, yet the precise mechanisms of cell death in the central nervous system have been elusive. An understanding of the how and why of cell death from Rift Valley fever virus (RVFV) infection may guide the design of therapeutic interventions. Here, we use primary neurons to probe the mechanism of cell death following RVFV infection. We found that RVFV triggers multiple cell death pathways both in the brains of animals that succumb to lethal RVFV encephalitis as well as in\n                        <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                        neuronal cultures. Induction of cell death occurs even with infection by an attenuated vaccine strain. These findings provide a platform for understanding cell death mechanisms caused by RVFV infection and identifying therapeutics that support neuron integrity during viral encephalitis.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01742-25","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:00:32Z","timestamp":1769090432000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Rift Valley fever virus activates multiple cell death pathways in neurons"],"prefix":"10.1128","volume":"100","author":[{"given":"Kaleigh A.","family":"Connors","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Disease and Microbiology, School of Public Health, University of Pittsburgh","place":["Pittsburgh, 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