TY - JOUR
T1 - Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner
AU - Popkin, Daniel L.
AU - Teijaro, John R.
AU - Sullivan, Brian M.
AU - Urata, Shuzo
AU - Rutschmann, Sophie
AU - De La Torre, Juan Carlos
AU - Kunz, Stefan
AU - Beutler, Bruce
AU - Oldstone, Michael
N1 - Funding Information:
This is Publication 20942 from the Departments of Immunology and Microbial Science and Genetics, The Scripps Research Institute, La Jolla, CA. Our work was supported by National Institutes of Health grants as follows: Training Grant AI007244 (to D.L.P.), AI070167 (to B.B.), and AI09484 and AI70967 (to M.B.A.O).
PY - 2011/3/17
Y1 - 2011/3/17
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2011.02.006
DO - 10.1016/j.chom.2011.02.006
M3 - Article
C2 - 21402360
AN - SCOPUS:79952660523
SN - 1931-3128
VL - 9
SP - 212
EP - 222
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -