Hirai Yuichi, Takemoto Ryuichi, Yanagi Yusuke, Shirogane Yuta
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Department of Molecular Virology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan.
J Virol. 2025 May 20;99(5):e0230724. doi: 10.1128/jvi.02307-24. Epub 2025 Apr 7.
Measles virus (MeV), an enveloped RNA virus belonging to the genus of the family , is the causative agent of measles, an acute febrile illness with skin rash. MeV has two types of envelope glycoproteins: the hemagglutinin (H) and fusion (F) protein. The H protein initially binds to its receptors, signaling lymphocytic activation molecule family member 1 (SLAMF1) and nectin-4, triggering conformational changes in the F protein that result in virus-to-cell or cell-to-cell membrane fusion. MeV may persist in the brain, which does not express SLAMF1 and nectin-4, leading to subacute sclerosing panencephalitis (SSPE) several years after acute infection. Recently, we have reported that MeV isolates from SSPE patients have hyperfusogenic amino acid changes (e.g., T461I) in the F protein, which enable MeV to spread in the brain by using cell adhesion molecule 1 (CADM1) and CADM2 as -acting fusion-triggering molecules. However, F proteins of SSPE isolates, such as the Patient B and OSA-3/Bs/B strains, carry additional changes besides T461I. In this study, we show that specific combinations of amino acid changes in the F proteins from SSPE isolates enable the induction of membrane fusion without CADM1/2 expression. We further demonstrate that these cumulative changes in the F protein allow the virus to exploit other fusion-triggering molecules than CADM1/2. These changes also promote efficient neuronal cell fusion. Our findings suggest that cumulative changes in the F protein may broaden the range of host factors capable of triggering cell fusion, facilitating MeV spread in the brain of SSPE patients.IMPORTANCESubacute sclerosing panencephalitis (SSPE) is a fatal disease caused by persistent infection of measles virus (MeV) in the brain. There is no effective therapy for the disease. MeV isolates from SSPE patients accumulate multiple amino acid changes in the F protein, including hyperfusogenic changes such as the T461I substitution, which allow MeV to spread in the brain by utilizing cell adhesion molecule 1 (CADM1) and CADM2 as -acting fusion-triggering molecules. In this study, we show that F proteins of SSPE isolates harboring additional changes besides T461I can induce membrane fusion independently of CADM1 and CADM2. The data also indicate that cumulative changes in the F protein may enable MeV to use other fusion-triggering host molecules than CADM1 and CADM2, facilitating its spread in the brain of SSPE patients. The findings deepen our understanding of the molecular mechanism underlying MeV neuropathogenicity in SSPE.
麻疹病毒（MeV）是一种包膜RNA病毒，属于该科属，是麻疹的病原体，麻疹是一种伴有皮疹的急性发热性疾病。MeV有两种包膜糖蛋白：血凝素（H）蛋白和融合（F）蛋白。H蛋白最初与其受体——信号淋巴细胞激活分子家族成员1（SLAMF1）和nectin-4结合，触发F蛋白的构象变化，导致病毒与细胞或细胞与细胞膜融合。MeV可能在不表达SLAMF1和nectin-4的大脑中持续存在，在急性感染数年之后导致亚急性硬化性全脑炎（SSPE）。最近，我们报道了从SSPE患者分离出的MeV毒株在F蛋白中具有高融合性氨基酸变化（例如T461I），这使得MeV能够通过使用细胞黏附分子1（CADM1）和CADM2作为融合触发分子在大脑中传播。然而，SSPE分离株的F蛋白，如患者B和OSA-3/Bs/B毒株，除了T461I之外还携带其他变化。在本研究中，我们表明，SSPE分离株F蛋白中特定的氨基酸变化组合能够在不表达CADM1/2的情况下诱导膜融合。我们进一步证明，F蛋白中的这些累积变化使病毒能够利用CADM1/2以外的其他融合触发分子。这些变化还促进了高效的神经元细胞融合。我们的研究结果表明，F蛋白中的累积变化可能拓宽了能够触发细胞融合的宿主因子范围，促进了MeV在SSPE患者大脑中的传播。重要性亚急性硬化性全脑炎（SSPE）是由麻疹病毒（MeV）在大脑中持续感染引起的致命疾病。该疾病没有有效的治疗方法。从SSPE患者分离出的MeV毒株在F蛋白中积累了多个氨基酸变化，包括T461I替代等高融合性变化，这使得MeV能够通过利用细胞黏附分子1（CADM1）和CADM2作为融合触发分子在大脑中传播。在本研究中，我们表明，除了T461I之外还携带其他变化的SSPE分离株F蛋白能够独立于CADM1和CADM2诱导膜融合。数据还表明，F蛋白中的累积变化可能使MeV能够使用CADM1和CADM2以外的其他融合触发宿主分子，促进其在SSPE患者大脑中的传播。这些发现加深了我们对SSPE中MeV神经致病性分子机制的理解。
