title: Measles virus mutants possessing the fusion protein with enhanced fusion activity spread effectively in neuronal cells, but not in other cells, without causing strong cytopathology.
abstract: Subacute sclerosing panencephalitis (SSPE) is caused by persistent measles virus (MV) infection in the central nervous system (CNS). Since human neurons, its main target cells, do not express known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), it remains to be understood how MV infects and spreads in them. We have recently reported that fusion-enhancing substitutions in the extracellular domain of the MV fusion (F) protein (T461I and S103I/N462S/N465S), which are found in multiple SSPE virus isolates, promote MV spread in human neuroblastoma cell lines and brains of suckling hamsters. In this study, we show that hyperfusogenic viruses with these substitutions also spread efficiently in human primary neuron cultures without inducing syncytia. These substitutions were found to destabilize the prefusion conformation of the F protein trimer, thereby enhancing fusion activity. However, these hyperfusogenic viruses exhibited stronger cytopathology and produced lower titers at later time points in SLAM- or nectin 4-expressing cells compared to the wild-type MV. Although these viruses spread efficiently in the brains of SLAM knock-in mice, they did not in the spleens. Taken together, the results suggest that enhanced fusion activity is beneficial for MV to spread in neuronal cells where no cytopathology occurs, but detrimental to other types of cells due to strong cytopathology. Acquisition of enhanced fusion activity through substitutions in the extracellular domain of the F protein may be crucial for MV's extensive spread in the CNS and development of SSPE.
  
  
  OBJECTIVE
  Subacute sclerosing panencephalitis (SSPE) is a fatal disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). Its cause is not well understood, and no effective therapy is currently available. Recently, we have reported that enhanced fusion activity of MV through the mutations in its fusion protein is a major determinant of efficient virus spread in human neuronal cells and brains of suckling hamsters. In this study, we show that those mutations render the conformation of the fusion protein less stable, thereby making it hyperfusogenic. Our results also show that enhanced fusion activity is beneficial for MV to spread in the CNS but detrimental to other types of cells in peripheral tissues, which are strongly damaged by the virus. Our findings provide important insight into the mechanism for the development of SSPE after MV infection.
authors.affiliation: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan wshunpei@virology.med.kyushu-u.ac.jp yyanagi@virology.med.kyushu-u.ac.jp.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Shirogane
authors.affiliation: Department of Neuropathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.affiliation: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Koga
authors.affiliation: Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan wshunpei@virology.med.kyushu-u.ac.jp yyanagi@virology.med.kyushu-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000821:virology*; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D050505:Mutant Proteins; D014760:Viral Fusion Proteins