{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:17:34Z","timestamp":1791389854902,"version":"4.3.3"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2025,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (Mtb) is a highly adapted human pathogen capable of manipulating host immunity. This study demonstrates that PPE19, a member of the PE\/PPE protein family, facilitates Mtb adhesion to, and invasion of murine macrophages. PPE19-coated microspheres showed enhanced uptake by macrophages compared to control beads, while Mtb overexpressing\n                      <jats:italic toggle=\"yes\">ppe19<\/jats:italic>\n                      (Rv1361c) was phagocytosed at a significantly greater rate than WT Mtb.\n                      <jats:italic toggle=\"yes\">ppe19<\/jats:italic>\n                      is identified as pH responsive and displays reduced expression following macrophage entry. CRISPR interference-mediated knockdown of two highly related PPE proteins,\n                      <jats:italic toggle=\"yes\">ppe18<\/jats:italic>\n                      (Rv1196) and\n                      <jats:italic toggle=\"yes\">ppe60<\/jats:italic>\n                      (Rv3478), revealed an additive reduction in Mtb\u2019s ability to invade host macrophages, indicating a potential functional relationship. Furthermore, the absence of an\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      phenotype following murine infection with a\n                      <jats:italic toggle=\"yes\">ppe19<\/jats:italic>\n                      knockout strain suggests functional redundancy within this PPE protein family. Finally, PE13 has been identified here as a binding partner for PPE19, characterizing another relationship presumed important for successful PPE secretion. These findings reveal PPE19 as a secreted effector protein used by Mtb to modulate important early interactions with the innate immune system, enhancing entry into host macrophages.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Tuberculosis remains a leading infectious disease killer worldwide, with approximately one-quarter of the global population infected with\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        (Mtb). Understanding how this pathogen initially establishes infection is crucial for developing more effective vaccines and treatments. This study identifies PPE19, a previously uncharacterized bacterial protein, as a key factor that helps Mtb invade and colonize human immune cells called macrophages during the earliest stages of infection. The research shows that PPE19 acts like a molecular \u201ckey\u201d that facilitates bacterial entry into host cells but is then downregulated once the bacteria are safely inside. Importantly, PPE19 belongs to a family of similar proteins that can compensate for each other, explaining why targeting individual members may not be sufficient for treatment. These findings provide new insights into tuberculosis pathogenesis and suggest that early infection factors like PPE19 could serve as targets for next-generation vaccines designed to prevent initial infection rather than just disease progression.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00036-25","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T13:00:14Z","timestamp":1754917214000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of PPE19 as a novel mediator of\n                    <i>Mycobacterium tuberculosis<\/i>\n                    -macrophage interactions"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6454-0351","authenticated-orcid":false,"given":"Christopher J.","family":"De Voss","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9946-519X","authenticated-orcid":false,"given":"Sean N.","family":"Riek","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miljan","family":"Stupar","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lendl","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2264-4785","authenticated-orcid":true,"given":"Brian M.","family":"Forde","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland","place":["Brisbane, Australia"]},{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]},{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"Australian Infectious Disease Research Centre, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0955-9890","authenticated-orcid":true,"given":"Nicholas P.","family":"West","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland","place":["Brisbane, Australia"]},{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"Australian Infectious Disease Research Centre, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","unstructured":"World Health Organization. 2023. Global tuberculosis report 2023. World Health Organization. https:\/\/www.who.int\/teams\/global-programme-on-tuberculosis-and-lung-health\/tb-reports\/global-tuberculosis-report-2023."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.26.2.167-200.1933"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00763-4"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22343-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12981"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/31159"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-6-95"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep39706"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051686"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801143"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav5912"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12109-5"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00540-18"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9030603"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5956"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12030"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00040"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep46716"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fob.2014.09.001"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resmic.2016.06.004"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000200RR"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.133"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00549-21"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02974-21"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2001-2-10-research0044"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.802645"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602606103"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119453109"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1909953"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052601"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000773"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201848071"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.001696"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.7.3614"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.160.3.1290"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.593"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401657101"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8303277"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109201108"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2007.09.006"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008448"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.150.7.2920"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.144.7.2771"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12264"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2016.274"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000174"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602817103"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/fty037"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.18.0173"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.05249-11"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12952"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/bab.1411"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.594288"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.228700"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12462"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-014-1243-1"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031237"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2013.12.016"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.618414"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2004.04.016"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12770"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1409345111"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003586"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.5146"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth996"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23893-3"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45343-7"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00036-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00036-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T13:02:29Z","timestamp":1759237349000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msphere.00036-25"}},"subtitle":[],"editor":[{"given":"Christina L.","family":"Stallings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":68,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9,30]]}},"alternative-id":["10.1128\/msphere.00036-25"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00036-25","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"2025-01-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00036-25"}}