title: Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus.
abstract: Multiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections.
  
  
  OBJECTIVE
  Filoviruses, including Ebola and Marburg viruses, cause rapidly fatal diseases in humans and nonhuman primates. There are currently no approved vaccines or therapeutics for filovirus diseases. In general, the cellular entry step of viruses is one of the key mechanisms to develop antiviral strategies. However, the molecular mechanisms underlying the entry process of filoviruses have not been fully understood. In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for filovirus entry, interact in the intracellular vesicles where Ebola virus GP-mediated membrane fusion occurs and that this interaction is important for filovirus infection. We found that filovirus infection and GP-mediated membrane fusion in cultured cells were remarkably suppressed by treatment with a TIM-1-specific monoclonal antibody that interfered with the interaction between TIM-1 and NPC1. Our data provide new insights for the development of antiviral compounds that can be universally used against filovirus infections.
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Makoto
authors: M
authors: Kuroda
authors: Division of Infection and Immunity, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Daisuke
authors: D
authors: Fujikura
authors: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Asuka
authors: A
authors: Nanbo
authors: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors: Andrea
authors: A
authors: Marzi
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Osamu
authors: O
authors: Noyori
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Masahiro
authors: M
authors: Kajihara
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Junki
authors: J
authors: Maruyama
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Keita
authors: K
authors: Matsuno
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Hiroko
authors: H
authors: Miyamoto
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan.
authors: Reiko
authors: R
authors: Yoshida
authors: Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
authors: Heinz
authors: H
authors: Feldmann
authors: Division of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo, Japan Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, Japan atakada@czc.hokudai.ac.jp.
authors: Ayato
authors: A
authors: Takada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000276:immunology / Q000302:isolation & purification; D002460:Cell Line; D002521:Cercopithecus; D029043:Ebolavirus / Q000502:physiology*; D006801:Humans; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D011991:Receptors, Virus