{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T18:48:05Z","timestamp":1775069285622,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Blakstad Maarschalk og Helbings legat for bekjempelse av tuberkulose og kreft","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Primary TB and post-primary TB (PPTB) are different disease entities. PPTB occurs only in humans, and no animal model mimics the actual pathology of PPTB. Information on the immune pathogenesis of PPTB is lacking due to the scarcity of untreated human material. In the early stages of PPTB, lesions can either progress or regress. Mycobacterial proteins present in these early lesions are vital to identifying targets for future development of better vaccines and therapeutics. Using proteomics, we aimed to establish a methodology to identify mycobacterial proteins expressed in lesions of human PPTB from the archival formalin-fixed and paraffin-embedded lung tissue from 1937\u22121941. Five untreated TB patients with a total of eleven samples were used. Micro-dissected tissue from six early and five necrotic lesions were processed for proteomics. Using a mass spectrometry and multiplexing tandem-mass-tag (TMT) approach, a total of 3531\n                    <jats:italic>Homo sapiens<\/jats:italic>\n                    and 110 bacterial proteins were identified and quantified. Four M. tuberculosis proteins; mIHF (accession p71658), groEL2 (accession P9WPE7), RV2971 (accession P9WQA5), cycA (accession O33203), and 1\n                    <jats:italic>Mycobacterium avium<\/jats:italic>\n                    protein hup (accession A0A0H3A054) were identified. Comparison of early lesions with necrotic lesions showed significantly more RV2971 proteins expressed in early lesions, and mIHF expressed in necrotic lesions (Log2 fold change necrotic \u2013 early; 1.401 &amp; \u22120.581 respectively). In conclusion, we established the methodology and proof of principle for detecting\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    proteins in PPTB lesions at different stages of the disease. We identified four\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    proteins, two showing significant differential expression in early and necrotic lesions.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0345052","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:34:01Z","timestamp":1775064841000},"page":"e0345052","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A meta-proteomics approach using autopsy material from the pre-antibiotic era from patients with untreated pulmonary tuberculosis to identify proteins present in early lesions of post-primary tuberculosis"],"prefix":"10.1371","volume":"21","author":[{"given":"Beatrice","family":"Normann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3485-5780","authenticated-orcid":true,"given":"Syeda Mariam","family":"Riaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisbet","family":"Sviland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9822-1191","authenticated-orcid":true,"given":"Tehmina","family":"Mustafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Even","family":"Birkeland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"issue":"1","key":"pone.0345052.ref001","doi-asserted-by":"crossref","DOI":"10.1016\/S2666-5247(22)00359-7","article-title":"WHO\u2019s global tuberculosis report 2022","volume":"4","author":"S Bagcchi","year":"2023","journal-title":"The Lancet Microbe"},{"issue":"4204","key":"pone.0345052.ref002","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.2.4204.154","article-title":"Origin, diagnosis, and management of early bronchogenic tuberculosis","volume":"2","author":"GG Kayne","year":"1941","journal-title":"Br Med J"},{"key":"pone.0345052.ref003","first-page":"25","article-title":"Pathogenesis of pulmonary tuberculosis","volume":"125","author":"Jr Dannenberg AM","year":"1982","journal-title":"Am Rev Respir Dis"},{"key":"pone.0345052.ref004","first-page":"248","article-title":"Observations of the pathogenesis of tuberculosis","volume":"39","author":"HK Dunham","year":"1923","journal-title":"Transactions of the American Climatological and Clinical Association"},{"key":"pone.0345052.ref005","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.tube.2015.11.010","article-title":"Tuberculosis as a three-act play: a new paradigm for the pathogenesis of pulmonary tuberculosis","volume":"97","author":"RL Hunter","year":"2016","journal-title":"Tuberculosis (Edinb)"},{"issue":"1","key":"pone.0345052.ref006","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0366-0850(35)80073-2","article-title":"Assmann\u2019s focus","volume":"29","author":"P Kerley","year":"1935","journal-title":"British Journal of Tuberculosis"},{"issue":"5","key":"pone.0345052.ref007","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0041-3879(24)80019-3","article-title":"X-ray observations of the pathogenesis of pulmonary tuberculosis","volume":"5","author":"HK Dunham","year":"1924","journal-title":"Tubercle"},{"issue":"12","key":"pone.0345052.ref008","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.3390\/pathogens12121426","article-title":"Novel insights into the pathogenesis of human post-primary tuberculosis from archival material of the pre-antibiotic era, 1931\u20131947","volume":"12","author":"SM Riaz","year":"2023","journal-title":"Pathogens"},{"issue":"12","key":"pone.0345052.ref009","doi-asserted-by":"crossref","first-page":"4839","DOI":"10.4049\/jimmunol.1600279","article-title":"The Lung Microbiome, Immunity, and the Pathogenesis of Chronic Lung Disease","volume":"196","author":"DN O\u2019Dwyer","year":"2016","journal-title":"J Immunol"},{"issue":"5","key":"pone.0345052.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01420-18","article-title":"The microbiome and tuberculosis: early evidence for cross talk","volume":"9","author":"S Namasivayam","year":"2018","journal-title":"mBio"},{"issue":"10","key":"pone.0345052.ref011","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/S2213-2600(18)30501-0","article-title":"The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda","volume":"7","author":"CC Naidoo","year":"2019","journal-title":"Lancet Respir Med"},{"issue":"4","key":"pone.0345052.ref012","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.trsl.2012.02.005","article-title":"The microbiome of the lung","volume":"160","author":"JM Beck","year":"2012","journal-title":"Transl Res"},{"key":"pone.0345052.ref013","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.3389\/fmicb.2019.03081","article-title":"Proteomic profiling reveals the architecture of granulomatous lesions caused by tuberculosis and mycobacterium avium complex lung disease","volume":"10","author":"S Seto","year":"2020","journal-title":"Front Microbiol"},{"key":"pone.0345052.ref014","unstructured":"Pahal P, Rajasurya V, Sharma S. Typical bacterial pneumonia. 2018."},{"key":"pone.0345052.ref015","article-title":"UniProt Consortium. UniProt: the universal protein knowledgebase in 2021","volume":"49","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pone.0345052.ref016","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nm.4073","article-title":"Inflammatory signaling in human tuberculosis granulomas is spatially organized","volume":"22","author":"MJ Marakalala","year":"2016","journal-title":"Nat Med"},{"issue":"1","key":"pone.0345052.ref017","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/imr.12252","article-title":"Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses","volume":"264","author":"A Lenaerts","year":"2015","journal-title":"Immunol Rev"},{"key":"pone.0345052.ref018","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1107\/S2053230X14007158","article-title":"A structural characterization of the isoniazid Mycobacterium tuberculosis drug target, Rv2971, in its unliganded form","volume":"70","author":"A Shahine","year":"2014","journal-title":"Acta Crystallogr F Struct Biol Commun"},{"issue":"4","key":"pone.0345052.ref019","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/03602530802431439","article-title":"The aldo-keto reductase superfamily and its role in drug metabolism and detoxification","volume":"40","author":"OA Barski","year":"2008","journal-title":"Drug Metab Rev"},{"issue":"6","key":"pone.0345052.ref020","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1046\/j.1365-3083.2001.01020.x","article-title":"Increased expression of fas ligand in human tuberculosis and leprosy lesions: a potential novel mechanism of immune evasion in mycobacterial infection","volume":"54","author":"T Mustafa","year":"2001","journal-title":"Scand J Immunol"},{"issue":"4","key":"pone.0345052.ref021","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1046\/j.1365-3083.2002.01140.x","article-title":"Increased Bcl-2 and reduced Bax expression in infected macrophages in slowly progressive primary murine Mycobacterium tuberculosis infection","volume":"56","author":"SJ Mogga","year":"2002","journal-title":"Scand J Immunol"},{"issue":"6","key":"pone.0345052.ref022","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1023\/A:1020286305950","article-title":"Increased expression of Fas ligand on Mycobacterium tuberculosis infected macrophages: a potential novel mechanism of immune evasion by Mycobacterium tuberculosis?","volume":"23","author":"T Mustafa","year":"1999","journal-title":"Inflammation"},{"issue":"1","key":"pone.0345052.ref023","doi-asserted-by":"crossref","first-page":"14214","DOI":"10.1038\/s41598-018-32340-2","article-title":"Essential nucleoid associated protein mihf (rv1388) controls virulence and housekeeping genes in mycobacterium tuberculosis","volume":"8","author":"NT Odermatt","year":"2018","journal-title":"Sci Rep"},{"key":"pone.0345052.ref024","first-page":"316","article-title":"Function of nucleoid-associated proteins in chromosome structuring and transcriptional regulation","volume":"24","author":"CJ Dorman","year":"2014","journal-title":"J Mol Microbiol Biotechnol"},{"issue":"26","key":"pone.0345052.ref025","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1021\/acs.biochem.5b00447","article-title":"Molecular dissection of mycobacterium tuberculosis integration host factor reveals novel insights into the mode of DNA binding and nucleoid compaction","volume":"54","author":"N Sharadamma","year":"2015","journal-title":"Biochemistry"},{"key":"pone.0345052.ref026","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1146\/annurev.mi.45.100191.001505","article-title":"The universally conserved GroE (Hsp60) chaperonins","volume":"45","author":"J Zeilstra-Ryalls","year":"1991","journal-title":"Annu Rev Microbiol"},{"issue":"2","key":"pone.0345052.ref027","doi-asserted-by":"crossref","DOI":"10.1093\/femspd\/ftv127","article-title":"Secretome profile analysis of hypervirulent Mycobacterium tuberculosis CPT31 reveals increased production of EsxB and proteins involved in adaptation to intracellular lifestyle","volume":"74","author":"F Vargas-Romero","year":"2016","journal-title":"Pathog Dis"},{"issue":"4","key":"pone.0345052.ref028","first-page":"481","article-title":"Mycobacterium tuberculosis Cpn60. 2 (GroEL2) blocks macrophage apoptosis via interaction with mitochondrial mortalin","volume":"6","author":"S Joseph","year":"2017","journal-title":"Biology Open"},{"issue":"2","key":"pone.0345052.ref029","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.00387-17","article-title":"Mycobacterium tuberculosis GroEL2 modulates dendritic cell responses","volume":"86","author":"M Georgieva","year":"2018","journal-title":"Infection and Immunity"},{"key":"pone.0345052.ref030","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1471-2377-6-34","article-title":"Detection of 65 kD heat shock protein in cerebrospinal fluid of tuberculous meningitis patients","volume":"6","author":"AV Mudaliar","year":"2006","journal-title":"BMC Neurol"},{"issue":"4","key":"pone.0345052.ref031","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.tube.2012.03.001","article-title":"Mycobacterium tuberculosis WhiB1 represses transcription of the essential chaperonin GroEL2","volume":"92","author":"MR Stapleton","year":"2012","journal-title":"Tuberculosis (Edinb)"},{"issue":"11","key":"pone.0345052.ref032","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1111\/j.1462-5822.2010.01496.x","article-title":"Mycobacterium tuberculosis employs Cpn60. 2 as an adhesin that binds CD43 on the macrophage surface","volume":"12","author":"TB Hickey","year":"2010","journal-title":"Cellular Microbiology"},{"key":"pone.0345052.ref033","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.tube.2018.09.007","article-title":"Cell death at the cross roads of host-pathogen interaction in Mycobacterium tuberculosis infection","volume":"113","author":"K Mohareer","year":"2018","journal-title":"Tuberculosis (Edinb)"},{"issue":"4","key":"pone.0345052.ref034","article-title":"Mycobacterial antigens accumulation in foamy macrophages in murine pulmonary tuberculosis lesions: Association with necrosis and making of cavities","volume":"91","author":"SM Riaz","year":"2020","journal-title":"Scand J Immunol"},{"key":"pone.0345052.ref035","doi-asserted-by":"crossref","unstructured":"Chen JM, Uplekar S, Gordon SV, Cole ST. A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. 2012.","DOI":"10.1371\/journal.pone.0043467"},{"issue":"12","key":"pone.0345052.ref036","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1093\/jac\/dkx316","article-title":"Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis","volume":"72","author":"J Chen","year":"2017","journal-title":"J Antimicrob Chemother"},{"key":"pone.0345052.ref037","first-page":"105","article-title":"Peptidoglycan","volume-title":"Molecular Medical Microbiology","author":"W Vollmer","year":"2015"},{"issue":"1","key":"pone.0345052.ref038","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1074\/mcp.M500178-MCP200","article-title":"Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach","volume":"5","author":"M Gr\u00f8nborg","year":"2006","journal-title":"Mol Cell Proteomics"},{"key":"pone.0345052.ref039","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/978-1-62703-360-2_14","article-title":"Informatics of protein and posttranslational modification detection via shotgun proteomics","volume":"1002","author":"JD Holman","year":"2013","journal-title":"Methods Mol Biol"},{"issue":"6","key":"pone.0345052.ref040","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.phrs.2007.04.012","article-title":"Proteomic technologies in the study of kinases: novel tools for the investigation of PKC in the heart","volume":"55","author":"G Agnetti","year":"2007","journal-title":"Pharmacol Res"},{"issue":"9","key":"pone.0345052.ref041","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1021\/acs.jproteome.2c00409","article-title":"In-depth mass spectrometry-based proteomics of formalin-fixed, paraffin-embedded tissues with a spatial resolution of 50-200 \u03bcm","volume":"21","author":"AJ Nwosu","year":"2022","journal-title":"J Proteome Res"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345052","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:34:08Z","timestamp":1775064848000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345052"}},"subtitle":[],"editor":[{"given":"Fumihiro","family":"Yamaguchi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0345052","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]}}}