A novel role for Stat1 in phagosome acidification and natural host resistance to intracellular infection by Leishmania major. Export

@article{citeulike:4547387, abstract = {Intracellular parasites of the genus Leishmania generate severe diseases in humans, which are associated with a failure of the infected host to induce a protective interferon gamma (IFNgamma)-mediated immune response. We tested the role of the JAK/STAT1 signaling pathway in Leishmania pathogenesis by utilizing knockout mice lacking the signal transducer and activator of transcription 1 (Stat1) and derived macrophages. Unexpectedly, infection of Stat1-deficient macrophages in vitro with promastigotes from Leishmania major and attenuated LPG1 knockout mutants (lpg(-)) specifically lacking lipophosphoglycan (LPG) resulted in a twofold increased intracellular growth, which was independent of IFNgamma and associated with a substantial increase in phagosomal pH. Phagosomes in Stat1-/- macrophages showed normal maturation as judged by the accumulation of the lysosomal marker protein rab7, and provided normal vATPase activity, but were defective in the anion conductive pathway required for full vesicular acidification. Our results suggest a role of acidic pH in the control of intracellular Leishmania growth early during infection and identify for the first time an unexpected role of Stat1 in natural anti-microbial resistance independent from its function as IFNgamma-induced signal transducer. This novel Stat1 function may have important implications to studies of other pathogens, as the acidic phagolysosomal pH plays an important role in antigen processing and the uncoating process of many viruses.}, author = {Sp\"{a}th, Gerald F. and Schlesinger, Paul and Schreiber, Robert and Beverley, Stephen M.}, citeulike-article-id = {4547387}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.ppat.1000381}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19381261}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19381261}, day = {17}, doi = {10.1371/journal.ppat.1000381}, issn = {1553-7374}, journal = {PLoS pathogens}, keywords = {acidification, leishmania, phagosome, spath09pdf, stat1}, month = {April}, number = {4}, pages = {e1000381+}, posted-at = {2009-05-19 23:28:42}, priority = {2}, publisher = {Public Library of Science}, title = {A novel role for Stat1 in phagosome acidification and natural host resistance to intracellular infection by Leishmania major.}, url = {http://dx.doi.org/10.1371/journal.ppat.1000381}, volume = {5}, year = {2009} }

TY - JOUR ID - citeulike:4547387 L3 - citeulike-article-id:4547387 N2 - Intracellular parasites of the genus Leishmania generate severe diseases in humans, which are associated with a failure of the infected host to induce a protective interferon gamma (IFNgamma)-mediated immune response. We tested the role of the JAK/STAT1 signaling pathway in Leishmania pathogenesis by utilizing knockout mice lacking the signal transducer and activator of transcription 1 (Stat1) and derived macrophages. Unexpectedly, infection of Stat1-deficient macrophages in vitro with promastigotes from Leishmania major and attenuated LPG1 knockout mutants (lpg(-)) specifically lacking lipophosphoglycan (LPG) resulted in a twofold increased intracellular growth, which was independent of IFNgamma and associated with a substantial increase in phagosomal pH. Phagosomes in Stat1-/- macrophages showed normal maturation as judged by the accumulation of the lysosomal marker protein rab7, and provided normal vATPase activity, but were defective in the anion conductive pathway required for full vesicular acidification. Our results suggest a role of acidic pH in the control of intracellular Leishmania growth early during infection and identify for the first time an unexpected role of Stat1 in natural anti-microbial resistance independent from its function as IFNgamma-induced signal transducer. This novel Stat1 function may have important implications to studies of other pathogens, as the acidic phagolysosomal pH plays an important role in antigen processing and the uncoating process of many viruses. IS - 4 JF - PLoS pathogens SN - 1553-7374 TI - A novel role for Stat1 in phagosome acidification and natural host resistance to intracellular infection by Leishmania major. PB - Public Library of Science VL - 5 SP - e1000381 KW - acidification KW - leishmania KW - phagosome KW - spath09pdf KW - stat1 AU - Späth, Gerald AU - Schlesinger, Paul AU - Schreiber, Robert AU - Beverley, Stephen PY - 2009/04/17/ UR - http://dx.doi.org/10.1371/journal.ppat.1000381 ER -