title: Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner.
abstract: The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), which naturally persists in rodents, represents a model for HIV, HBV, and HCV. Cleavage of the viral glycoprotein precursor by membrane-bound transcription factor peptidase, site 1 (Mbtps1 or site-1 protease), is crucial for the life cycle of arenaviruses and therefore represents a potential target for therapy. Recently, we reported a viable hypomorphic allele of Mbtps1 (woodrat) encoding a protease with diminished enzymatic activity. Using the woodrat allele, we examine the role of Mbtps1 during persistent LCMV infection. Surprisingly, Mbtps1 inhibition limits persistent but not acute viral infection and is associated with an organ/cell type-specific decrease in viral titers. Analysis of bone marrow-derived dendritic cells from woodrat mice supports their specific role in resolving persistent viral infection. These results support in vivo targeting of Mbtps1 in the treatment of arenavirus infections and demonstrate a critical role for dendritic cells in persistent viral infections.
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: popkind@scripps.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Popkin
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sullivan
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Urata
authors.affiliation: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rutschmann
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Torre
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.affiliation: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Oldstone
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000276:immunology / Q000821:virology; D000956:Antigens, Viral / Q000378:metabolism; D001117:Arenaviridae Infections / Q000276:immunology* / Q000821:virology; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate; D016867:Immunocompromised Host; D007668:Kidney / Q000276:immunology / Q000821:virology; D008099:Liver / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000254:growth & development / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D043484:Proprotein Convertases / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D010948:Viral Plaque Assay; D056189:Viral Tropism
chemical_list: D000956:Antigens, Viral; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1