title: Mutant fusion proteins with enhanced fusion activity promote measles virus spread in human neuronal cells and brains of suckling hamsters.
abstract: Subacute sclerosing panencephalitis (SSPE) is a fatal degenerative disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). From the genetic study of MV isolates obtained from SSPE patients, it is thought that defects of the matrix (M) protein play a crucial role in MV pathogenicity in the CNS. In this study, we report several notable mutations in the extracellular domain of the MV fusion (F) protein, including those found in multiple SSPE strains. The F proteins with these mutations induced syncytium formation in cells lacking SLAM and nectin 4 (receptors used by wild-type MV), including human neuronal cell lines, when expressed together with the attachment protein hemagglutinin. Moreover, recombinant viruses with these mutations exhibited neurovirulence in suckling hamsters, unlike the parental wild-type MV, and the mortality correlated with their fusion activity. In contrast, the recombinant MV lacking the M protein did not induce syncytia in cells lacking SLAM and nectin 4, although it formed larger syncytia in cells with either of the receptors. Since human neuronal cells are mainly SLAM and nectin 4 negative, fusion-enhancing mutations in the extracellular domain of the F protein may greatly contribute to MV spread via cell-to-cell fusion in the CNS, regardless of defects of the M protein.
authors.affiliation: Department of Virology and Department of Neuropathology, Kyushu University, Fukuoka, Japan. wshunpei@virology.med.kyushu-u.ac.jp
authors.forename: Shumpei
authors.initials: S
authors.lastname: Watanabe
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shirogane
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikegame
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Koga
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000821:virology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002459:Cell Fusion; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D015726:Giant Cells / Q000821:virology; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013344:Subacute Sclerosing Panencephalitis / Q000401:mortality / Q000821:virology; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D050505:Mutant Proteins; D011956:Receptors, Cell Surface; D014760:Viral Fusion Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1