{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:34:41Z","timestamp":1785843281415,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013041","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"reference-count":105,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Intracellular pathogens of <jats:italic>Salmonella<\/jats:italic> spp. survive and replicate within the phagosomes, called Salmonella-containing vacuoles (SCVs) inside macrophages by manipulating phagosomal maturation and phagolysosome formation. While controversies exist about the phagosomal traffic of <jats:italic>Salmonella<\/jats:italic> Typhimurium, little studies were carried out with the intracellular survival mechanisms of <jats:italic>Salmonella<\/jats:italic> Typhi (<jats:italic>S.<\/jats:italic> Typhi). We had previously reported that a eukaryote-like serine\/threonine kinase of <jats:italic>S.<\/jats:italic> Typhi (T4519) contributes to survival within macrophages and activates host pro-inflammatory signaling pathways regulated by NF-\u03baB. However, neither the mechanisms underlying NF-\u03baB activation nor how it contributes to intracellular survival of <jats:italic>S.<\/jats:italic> Typhi were studied. Here we show, by using antibody-mediated blocking and gene knockdown studies that T4519 activates Toll-like receptor 2 (TLR2) signals in the human monocyte-derived macrophages. We computationally predicted the NH2-terminal glycine rich repeat domain of T4519 as the TLR2-binding moiety and confirmed the interaction by co-immunoprecipitation experiment. TLR2-T4519 interaction transcriptionally repressed cystatin B, a cathepsin B inhibitor, leading to the activation of cytosolic cathepsin B, leaked from the lysosomes of the infected cells. Through a series of RT-qPCR, western blotting, gene knockdown, flow cytometry and confocal microscopy experiments, we have shown that active cytosolic cathepsin B cleaves IKB-\u03b1, resulting in nuclear translocation of NF-\u03baB and transactivation of its target genes, including reactive oxygen species (ROS), which in turn induces lysosomal membrane permeabilization (LMP). TLR2-dependent targeting of the cystatin B-cathepsin B-NF-\u03baB-ROS pathways by T4519, leading to LMP promotes phagosomal survival of <jats:italic>S.<\/jats:italic> Typhi. This study describes a unique mechanism of the exploitation of host NF-\u03baB signaling pathways by bacterial pathogens to promote its own persistence within macrophage cells.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013041","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T21:58:34Z","timestamp":1743544714000},"page":"e1013041","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Salmonella Typhi serine threonine kinase T4519 induces lysosomal membrane permeabilization by manipulating Toll-like receptor 2-Cystatin B-Cathepsin B-NF-\u03baB-reactive oxygen species pathway and promotes survival within human macrophages"],"prefix":"10.1371","volume":"21","author":[{"given":"Swarnali","family":"Chakraborty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debayan","family":"Ganguli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theeya","family":"Nagaraja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Animesh","family":"Gope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudip","family":"Dey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ananda","family":"Pal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul Shubhra","family":"Mandal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipta Sekhar","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-469X","authenticated-orcid":true,"given":"Santasabuj","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"issue":"2","key":"ppat.1013041.ref001","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0304-4165(68)90015-9","article-title":"Inhibition of bacteria by lactoferrin and other iron-chelating agents","volume":"170","author":"JD Oram","year":"1968","journal-title":"Biochim Biophys Acta"},{"issue":"14\u201315","key":"ppat.1013041.ref002","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1016\/j.micinf.2007.09.006","article-title":"Nramp1 phagocyte intracellular metal withdrawal defense","volume":"9","author":"MF Cellier","year":"2007","journal-title":"Microbes 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