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: Daniel L Popkin, John R Teijaro, Brian M Sullivan, Shuzo Urata, Sophie Rutschmann, Juan Carlos de la Torre, Stefan Kunz, Bruce Beutler, Michael Oldstone
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 9 Issue 3 Pg. 212-222 (Mar 17 2011) ISSN: 1934-6069 [Electronic] United States
• PMID: 21402360 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Viral
• Proprotein Convertases
• Serine Endopeptidases
• membrane-bound transcription factor peptidase, site 1

Topics

• Animals
• Animals, Genetically Modified (immunology, virology)
• Antigens, Viral (metabolism)
• Arenaviridae Infections (immunology, virology)
• B-Lymphocytes (immunology)
• Bone Marrow Cells (immunology, virology)
• Dendritic Cells (immunology)
• Immunity, Innate
• Immunocompromised Host
• Kidney (immunology, virology)
• Liver (immunology, virology)
• Lymphocytic choriomeningitis virus (growth & development, physiology)
• Mice
• Mice, Inbred C57BL
• Mutation
• Proprotein Convertases (genetics, immunology)
• Serine Endopeptidases (genetics, immunology)
• Spleen (immunology, virology)
• T-Lymphocytes (immunology)
• Viral Plaque Assay
• Viral Tropism