Amino acid changes accumulated in the fusion protein allow neuropathogenic measles viruses to use a broad repertoire of host factors for cell fusion triggering

Measles virus (MeV), an enveloped RNA virus belonging to the genus <i>Morbillivirus</i> of the family <i>Paramyxoviridae</i>, 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 <i>cis</i>-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 <i>cis</i>-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.