{"doi":"10.1002/jmv.29949","title":"A1‐reactive astrocytes and IFNAR signaling collectively induce neuronal cell death during infection of IFNAR1−/− mice by severe fever with thrombocytopenia syndrome virus","abstract":"Severe fever with thrombocytopenia syndrome (SFTS) is caused by the SFTS virus (SFTSV), a bunyavirus that is endemic throughout eastern Asia. SFTSV was first discovered in 2009 in central China1 and has since infected about 5500 people in China2 and approximately 800 each in Japan and South Korea.3 The disease (SFTS) is characterized by fever, thrombocytopenia, and central nervous system (CNS) symptoms including headache, vertigo, coma, and encephalitis4, 5 which has impacted as many as 45% of SFTS patients.6 The mortality rate caused by SFTSV infection varies by region and by year with reported rates as high as 27%.7, 8 There are currently no therapeutics or vaccines available for SFTS treatment and prevention. While clinical manifestations such as decreased blood flow to the brain resulting from systemic SFTSV infection likely contribute to the disease pathology,9, 10 some studies have shown that direct viral infection of the brain may also play an important role in disease pathogenesis. Evidence from a newborn mouse-infection model has shown that SFSTV can infect microglia to cause inflammasome-mediated neuronal cell death,11 which could in part explain how some immunocompromised individuals are more likely to develop severe disease as a result of the infection,4-6 whereas most patients who succumb to SFTS show symptoms of severe encephalitis before death. Nevertheless, the molecular mechanisms of virus-induced neuronal pathogenesis and the location of virus-induced brain damage have not been fully characterized. Kim et al. have recently published a paper in Journal of Medical Virology,12 in which they infected the interferon-alpha receptor knock-out (IFNAR1−/−) adult mice intraperitoneally with SFTSV to deliver the virus systematically and to show that the virus could successfully cross the blood–brain barrier (BBB) to invade the CNS as evidenced by the presence of the viral protein and genomic content being detectable throughout the CNS 4 days after the infection. They showed that SFTSV infected the brainstem and spinal cord of the IFNAR1−/− mice and that A1-reactive astrocytes were activated by virus infection, leading to neuronal cell death. Because the brainstem and spinal cord are regions of the brain that have been associated with respiratory function and motor neurons in IFNAR1−/− mice, SFTSV infection leading to lethal neuroinflammation and neuronal cell death may underlie the cause of disease pathogenesis, pathology, and mortality of some SFTS patients. Specifically, the authors showed that viral gene expressions were significantly higher in the olfactory bulb, cortex, cerebellum, brainstem, and spinal cord of the IFNAR1−/− mice. They also characterized the immunological effects of SFTSV infection of the brain and showed that IFNAR deficiency also increased neuronal cell death as demonstrated by a significant decrease in viable neurons by Day-4 postinfection. They showed decreased expression levels of most tested pro-inflammatory cytokines, such as IFNγ, interleukin (IL)1α, IL1β, IL6, and tumor necrosis factor-α. Two exceptions were C1q and C3 cytokines, which were higher in the virus-infected IFNAR1−/− mice. Because these two cytokines have been implicated in the activation of the A1-reactive astrocytes, the authors expanded on this finding by investigating astrocyte signaling and found significantly higher levels of activated astrocytes and A1-astrocyte gene expression in the virus-infected IFNAR1−/− mice. The authors also showed that primary astrocytes of SFTSV-infected IFNAR1−/− mice also induced neuronal cell death through the activation of A1-reactive astrocytes. To do this, they investigated the interactions between infected neurons and microglia or astrocytes by isolating primary neurons, microglia, and astrocytes from embryonic or neonatal wild type (WT) and IFNAR1−/− mouse pups and infecting those cells with SFTSV in culture and incubating the infected neurons with the cell-culture media supernatant coll","journal":"Journal of Medical Virology","year":2024,"id":472046,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":233282,"name":"Hinh Ly","orcid":"0000-0001-8271-2033","position":1,"is_corresponding":false},{"id":233278,"name":"Morgan Brisse","orcid":"0000-0002-7040-4495","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T02:05:53.032464Z","pmid":"39350645","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}