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Published on: December 21, 2019
Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific
Daniel L Popkin1, John R Teijaro2, Brian M Sullivan2
1Department 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.
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.
Insights
Inhibiting the Mbtps1 protease limits persistent lymphocytic choriomeningitis virus (LCMV) infection by targeting specific cells. Dendritic cells play a key role in resolving chronic viral infections.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Lymphocytic choriomeningitis virus (LCMV) is a model arenavirus for persistent infections like HIV, HBV, and HCV.
- Cleavage of the viral glycoprotein precursor by membrane-bound transcription factor peptidase, site 1 (Mbtps1) is essential for arenavirus replication.
- Mbtps1 is a potential therapeutic target for arenavirus infections.
Purpose of the Study:
- To investigate the role of Mbtps1 in persistent LCMV infection using a hypomorphic allele (woodrat).
- To determine the effect of Mbtps1 inhibition on acute versus persistent viral infections.
- To elucidate the contribution of specific cell types, such as dendritic cells, in resolving persistent LCMV infection.
Main Methods:
- Utilizing a hypomorphic Mbtps1 (woodrat) allele in mice to study LCMV infection.
- Comparing viral titers during acute and persistent LCMV infection following Mbtps1 inhibition.
- Analyzing the function of bone marrow-derived dendritic cells from woodrat mice during LCMV infection.
Main Results:
- Mbtps1 inhibition significantly limits persistent LCMV infection but not acute infection.
- Viral titers decreased in an organ/cell type-specific manner upon Mbtps1 inhibition.
- Bone marrow-derived dendritic cells from woodrat mice demonstrated a crucial role in resolving persistent LCMV infection.
Conclusions:
- Targeting Mbtps1 in vivo is a promising therapeutic strategy for treating arenavirus infections.
- Dendritic cells are critical players in the resolution of persistent viral infections.
- Mbtps1 activity differentially impacts acute and persistent stages of arenavirus infection.
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