{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:46:16Z","timestamp":1785415576500,"version":"3.56.0"},"reference-count":77,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM139486"],"award-info":[{"award-number":["GM139486"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      After ingestion into macrophage phagosomes, some bacterial pathogens such as\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      ) evade killing by preventing phagosome acidification and fusion of the phagosome with a lysosome.\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      accumulates extracellular polyphosphate (polyP), and polyP inhibits macrophage phagosome acidification and bacterial killing. In\n                      <jats:italic toggle=\"yes\">Dictyostelium discoideum<\/jats:italic>\n                      , polyP also inhibits bacterial killing, and we identified some proteins in\n                      <jats:italic toggle=\"yes\">D. discoideum<\/jats:italic>\n                      that polyP requires to suppress the killing of ingested bacteria. Here, we find that pharmacological inhibition of human orthologues of the\n                      <jats:italic toggle=\"yes\">D. discoideum<\/jats:italic>\n                      proteins, including P2Y1 receptors, mammalian target of rapamycin, and inositol hexakisphosphate kinase, enhances the killing of\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Legionella pneumophila<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Listeria monocytogenes<\/jats:italic>\n                      by human macrophages.\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      inhibits phagosome acidification, expression of the proinflammatory marker CD54, and autophagy and increases expression of the anti-inflammatory marker CD206. In\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      -infected macrophages, the polyP-degrading enzyme polyphosphatase (ScPPX) and inhibitors reversed these effects, with ScPPX increasing CD54 expression more in female macrophages compared to male macrophages. In addition,\n                      <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                      inhibits proteasome activity, and some, but not all, inhibitors reversed these effects. While the existence of a dedicated polyP signaling pathway remains uncertain, our findings suggest that pharmacological inhibition of select host proteins can restore macrophage function and enhances the killing of intracellular pathogens.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Human macrophages engulf bacteria into phagosomes, which then fuse with lysosomes to kill the bacteria. However, after engulfment, pathogenic bacteria such as\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Legionella pneumophila<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Listeria monocytogenes<\/jats:italic>\n                      can block phagosome-lysosome fusion, allowing their survival. Here, we show that pharmacological inhibition of specific macrophage proteins reverses these effects and enhances bacterial killing. These findings suggest that targeting host factors involved in these processes may provide a therapeutic strategy to improve macrophage function against infections such as tuberculosis, Legionnaires\u2019 disease, and listeriosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02163-25","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T14:00:36Z","timestamp":1764770436000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacological inhibition of host pathways enhances macrophage killing of intracellular bacterial pathogens"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-1064","authenticated-orcid":true,"given":"Ramesh","family":"Rijal","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0270vfa57","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological, Environmental, and Earth Sciences, The University of Southern Mississippi","place":["Hattiesburg, USA"]},{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Texas A&M University","place":["College Station, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2361-4307","authenticated-orcid":true,"given":"Richard H.","family":"Gomer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Texas A&M University","place":["College Station, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.001021"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115653"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12266"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2128"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.16.8841"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25052898"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02284"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.126"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.07.028"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.77.083007.093039"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)38459-5"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.11.5818"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.154393"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.180.8.2186-2193.1998"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.060030097"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.170283397"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06925.x"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.70.5.3064-3072.2004"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011400"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385095-9.00015-4"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep26900"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00039-13"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05814.x"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00038-13"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2012009117"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1369763"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17639-x"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.3109\/10520297409117009"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00592-21"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.764733"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01939-23"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.5.3031-3037.2004"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-09-529602"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704673"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm990249v"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58642"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.2.815"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900752200"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0442"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2012.05.009"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1212324110"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01773-0"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1011"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.06.027"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.04.001"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3RU0316-144R"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01563-18"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20130014"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1345-4"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207345200"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0142-9612(97)00072-0"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-021-01437-2"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02072.x"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051239"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.44.27280"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(94)90462-6"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.133"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.51.1.314-319.1986"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2052"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1111\/brv.12392"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11101153"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.13188\/2325-4653.1000003"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.034"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060410-150257"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.593"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11040526"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01157"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2009.09.011"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120163297"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.274"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.01.012"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129.15.3657"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100845"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.2011.03486.x"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.36.2.362-366.1998"}],"container-title":["Microbiology Spectrum"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02163-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02163-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T14:08:48Z","timestamp":1767708528000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.02163-25"}},"subtitle":[],"editor":[{"given":"Travis","family":"Bourret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":77,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,6]]}},"alternative-id":["10.1128\/spectrum.02163-25"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.02163-25","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.04.06.647500","asserted-by":"object"}]},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]},"assertion":[{"value":"2025-07-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02163-25"}}