{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:38:02Z","timestamp":1793655482627,"version":"4.5.1"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rabies remains one of the most preventable fatal infections, yet once clinical symptoms appear, survival is exceedingly rare. This paradox cannot be explained simply by the absence of a single effective antiviral drug. In this review, we frame symptomatic rabies as a sequential barrier-driven disease process in which neuroinvasion, immune evasion, and blood\u2013brain barrier restriction converge to make post-symptom rescue biologically difficult. Rabies virus first changes the anatomical battlefield by entering peripheral nerves, exploiting receptor-supported uptake and retrograde axonal transport, and establishing infection within protected neural circuits. It then delays the host counterattack through weak or strain-dependent innate sensing, viral interference with interferon and signal transducer and activator of transcription (STAT) signaling, and insufficient conversion of peripheral immune activation into effective central nervous system clearance. Once central nervous system (CNS) infection is established, blood\u2013brain barrier restriction further limits access of neutralizing antibodies, antiviral compounds, biologics, and immune cells to infected neural tissue. The convergence of these barriers permits CNS persistence and drives fatal encephalopathy, characterized less by widespread neuronal destruction than by synaptic, dendritic, circuit, autonomic, and functional collapse. Recent experimental advances, including CNS-accessible antibody strategies, blood\u2013brain barrier (BBB)-modulating approaches, monoclonal antibody therapy, and One Medicine models, suggest that symptomatic rabies may require stage-specific therapeutic combinations rather than a single rescue intervention. We propose that future rabies therapy should be organized around three translational windows: preventing neuroinvasion before CNS entry, achieving immune-assisted viral control during early CNS infection, and combining CNS viral clearance with neuroprotective and autonomic support once encephalopathy is established. However, most mechanistic and therapeutic evidence remains derived from cellular and animal models, and clinical validation of CNS-directed or barrier-targeted interventions in symptomatic human rabies remains limited. Breaking the barrier cascade may be the central requirement for making symptomatic rabies treatable.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1904824","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:08:19Z","timestamp":1788520099000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Biological barriers underlying the extremely high fatality of symptomatic rabies: neuroinvasion, immune evasion, and blood\u2013brain barrier restriction"],"prefix":"10.3389","volume":"17","author":[{"given":"Chen","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Trauma Surgery, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Hospital for Infectious Diseases","place":["Wuhan, China"]},{"name":"Animal-Related Injury Treatment Center, Wuhan Jinyintan Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Hospital for Infectious Diseases","place":["Wuhan, China"]},{"name":"Animal-Related Injury Treatment Center, Wuhan Jinyintan Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Hospital for Infectious Diseases","place":["Wuhan, China"]},{"name":"Animal-Related Injury Treatment Center, Wuhan Jinyintan Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Hospital for Infectious Diseases","place":["Wuhan, China"]},{"name":"Animal-Related Injury Treatment Center, Wuhan Jinyintan Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology","place":["Wuhan, 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