{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:45:10Z","timestamp":1790959510465,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>There is an urgent need for accurate and sensitive diagnostic tools that can overcome the current challenge to distinguish individuals with latent tuberculosis infection (LTBI) from individuals with active tuberculosis (TB). Recent literature has suggested that a group of cytokines may serve as biomarkers of TB disease progression. Using a multiplex ELISA, we quantified 27 circulatory markers present within the unstimulated plasma of individuals in Durban, South Africa who were healthy (n=20), LTBI (n=13), or had active TB (n=30). RT-qPCR was performed to measure gene expression of the cytokines of interest, using RNA isolated from healthy (n=20), LTBI (n=20), or active TB (n=30). We found that at the protein level, IL-1RA, IL-6, and IP-10 were significantly more abundant in participants with active TB (p&amp;lt; 0.05) compared to those with LTBI individuals. IP-10 also showed the strongest association with active TB compared to healthy and LTBI at mRNA level. Our data shows that these proteins may serve as biomarkers of TB at both the protein and gene level.<\/jats:p>","DOI":"10.3389\/fcimb.2022.908144","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T05:53:52Z","timestamp":1653630832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Elevated IP-10 at the Protein and Gene Level Associates With Pulmonary TB"],"prefix":"10.3389","volume":"12","author":[{"given":"Kimone L.","family":"Fisher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denelle","family":"Moodley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerishka","family":"Rajkumar-Bhugeloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omolara O.","family":"Baiyegunhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farina","family":"Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hlumani","family":"Ndlovu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thumbi","family":"Ndung\u2019u","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohlopheni J.","family":"Marakalala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.micinf.2004.09.004","article-title":"IFN-Gamma-Inducible Protein 10 and Pentraxin 3 Plasma Levels Are Tools for Monitoring Inflammation and Disease Activity in Mycobacterium Tuberculosis Infection","volume":"7","author":"Azzurri","year":"2005","journal-title":"Microbes Infect."},{"key":"B2","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s12879-019-3738-4","article-title":"Test and Treat TB: A Pilot Trial of GeneXpert MTB\/RIF Screening on a Mobile HIV Testing Unit in South Africa","volume":"19","author":"Bassett","year":"2019","journal-title":"BMC Infect. Dis."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01456","article-title":"Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions","volume":"9","author":"Blauenfeldt","year":"2018","journal-title":"Front. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"105166","DOI":"10.1016\/j.meegid.2021.105166","article-title":"Cytokine Storm in Tuberculosis and IL-6 Involvement","volume":"97","author":"Boni","year":"2022","journal-title":"Infect. Genet. Evol."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043438","article-title":"Immune Responses to ESAT-6 and CFP-10 by FASCIA and Multiplex Technology for Diagnosis of M. Tuberculosis Infection; IP-10 Is a Promising Marker","volume":"7","author":"Borgstr\u00f6m","year":"2012","journal-title":"PloS One"},{"key":"B6","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.molimm.2014.06.002","article-title":"Alteration of Serum Inflammatory Cytokines in Active Pulmonary Tuberculosis Following Anti-Tuberculosis Drug Therapy","volume":"62","author":"Chowdhury","year":"2014","journal-title":"Mol. Immunol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01855","article-title":"A Model Based on the Combination of IFN-\u03b3, IP-10, Ferritin and 25-Hydroxyvitamin D for Discriminating Latent From Active Tuberculosis in Children","volume":"10","author":"Comella-Del-Barrio","year":"2019","journal-title":"Front. Microbiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1146\/annurev.immunol.021908.132703","article-title":"Cell-Mediated Immune Responses in Tuberculosis","volume":"27","author":"Cooper","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1183\/09031936.00115110","article-title":"Interferon-\u03b3 Release Assays for the Diagnosis of Latent Mycobacterium Tuberculosis Infection: A Systematic Review and Meta-Analysis","volume":"37","author":"Diel","year":"2011","journal-title":"Eur. Respir. J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"504","DOI":"10.5588\/ijtld.15.0048","article-title":"Advances in the Diagnosis of Tuberculosis: Current Status and Future Prospects","volume":"19","author":"Dorman","year":"2015","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1046\/j.1365-2567.2003.01600.x","article-title":"Macrophages Exposed to Mycobacterium Tuberculosis Release Chemokines Able to Recruit Selected Leucocyte Subpopulations: Focus on Gammadelta Cells","volume":"108","author":"Ferrero","year":"2003","journal-title":"Immunology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"57581","DOI":"10.18632\/oncotarget.11420","article-title":"Identification of Novel Host Biomarkers in Plasma as Candidates for the Immunodiagnosis of Tuberculosis Disease and Monitoring of Tuberculosis Treatment Response","volume":"7","author":"Jacobs","year":"2016","journal-title":"Oncotarget"},{"key":"B13","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1128\/JCM.02758-14","article-title":"Discrimination Between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production","volume":"53","author":"Jeong","year":"2015","journal-title":"J. Clin. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1164\/ajrccm.157.4.9709126","article-title":"Tumor Necrosis Factor and Interleukin-1 Inhibitors as Markers of Disease Activity of Tuberculosis","volume":"157","author":"Juffermans","year":"1998","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B15","unstructured":"KannabusA.\n          TB Statistics South Africa TBFACTS.org: 20212021"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.653898","article-title":"Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis","volume":"12","author":"Kumar","year":"2021","journal-title":"Front. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/s41598-018-19523-7","article-title":"Changes in Cytokine Responses to TB Antigens ESAT-6, CFP-10 and TB 7.7 and Inflammatory Markers in Peripheral Blood During Therapy","volume":"8","author":"Leem","year":"2018","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1084\/jem.20180325","article-title":"Type I Interferons in Tuberculosis: Foe and Occasionally Friend","volume":"215","author":"Moreira-Teixeira","year":"2018","journal-title":"J. Exp. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"5566","DOI":"10.1038\/s41467-020-19412-6","article-title":"Type I IFN Exacerbates Disease in Tuberculosis-Susceptible Mice by Inducing Neutrophil-Mediated Lung Inflammation and NETosis","volume":"11","author":"Moreira-Teixeira","year":"2020","journal-title":"Nat. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1146\/annurev-immunol-032712-095939","article-title":"The Immune Response in Tuberculosis","volume":"31","author":"O'Garra","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"16076","DOI":"10.1038\/nrdp.2016.76","article-title":"Tuberculosis","volume":"2","author":"Pai","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B22","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.drudis.2009.10.005","article-title":"The Quest for Biomarkers in Tuberculosis","volume":"15","author":"Parida","year":"2010","journal-title":"Drug Discov"},{"key":"B23","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1186\/s12879-020-05185-2","article-title":"Predictive Value of TNF-\u03b1, IFN-\u03b3, and IL-10 for Tuberculosis Among Recently Exposed Contacts in the United States and Canada","volume":"20","author":"Reichler","year":"2020","journal-title":"BMC Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1164\/rccm.200509-1516PP","article-title":"An Update on the Diagnosis of Tuberculosis Infection","volume":"174","author":"Richeldi","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1756-0500-2-19","article-title":"IP-10, MCP-1, MCP-2, MCP-3, and IL-1RA Hold Promise as Biomarkers for Infection With M. Tuberculosis in a Whole Blood Based T-Cell Assay","volume":"2","author":"Ruhwald","year":"2009","journal-title":"BMC Res. Notes"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002840","article-title":"Clinical, Microbiologic, and Immunologic Determinants of Mortality in Hospitalized Patients With HIV-Associated Tuberculosis: A Prospective Cohort Study","volume":"16","author":"Schutz","year":"2019","journal-title":"PloS Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1128\/microbiolspec.GPP3-0022-2018","article-title":"Immunology of Mycobacterium Tuberculosis Infections","volume":"7","author":"Sia","year":"2019","journal-title":"Microbiolol. Spectrum"},{"key":"B28","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1186\/2193-1801-2-686","article-title":"Interleukin-6: A Potent Biomarker of Mycobacterial Infection","volume":"2","author":"Singh","year":"2013","journal-title":"Springerplus"},{"key":"B29","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.jinf.2020.09.032","article-title":"Mycobacterium Tuberculosis-Specific Cytokine Biomarkers to Differentiate Active TB and LTBI: A Systematic Review","volume":"81","author":"Sudbury","year":"2020","journal-title":"J. Infect."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152483","article-title":"Combined Analysis of IFN-\u03b3, IL-2, IL-5, IL-10, IL-1RA and MCP-1 in QFT Supernatant Is Useful for Distinguishing Active Tuberculosis From Latent Infection","volume":"11","author":"Suzukawa","year":"2016","journal-title":"PloS One"},{"key":"B31","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1378\/chest.117.1.103","article-title":"Imbalances Between Tumor Necrosis Factor-Alpha and Its Soluble Receptor Forms, and Interleukin-1beta and Interleukin-1 Receptor Antagonist in BAL Fluid of Cavitary Pulmonary Tuberculosis","volume":"117","author":"Tsao","year":"2000","journal-title":"Chest"},{"key":"B32","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1111\/j.1749-6632.2012.06802.x","article-title":"The Dual Role of Biomarkers for Understanding Basic Principles and Devising Novel Intervention Strategies in Tuberculosis","volume":"1283","author":"Weiner","year":"2013","journal-title":"Ann. New York Acad. Sci."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003901","article-title":"Is IP-10 a Better Biomarker for Active and Latent Tuberculosis in Children Than IFNgamma","volume":"3","author":"Whittaker","year":"2008","journal-title":"PloS One"},{"key":"B34","unstructured":"World Health Organization: Global Tuberculosis Report 20212021"},{"key":"B35","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.tube.2017.07.013","article-title":"Multiplex Analysis of Plasma Cytokines\/Chemokines Showing Different Immune Responses in Active TB Patients, Latent TB Infection and Healthy Participants","volume":"107","author":"Yao","year":"2017","journal-title":"Tuberculosis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.cyto.2016.08.030","article-title":"Identification of Promising Plasma Immune Biomarkers to Differentiate Active Pulmonary Tuberculosis","volume":"88","author":"Zambuzi","year":"2016","journal-title":"Cytokine"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.908144\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T05:53:56Z","timestamp":1653630836000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.908144\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,27]]},"references-count":36,"alternative-id":["10.3389\/fcimb.2022.908144"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.908144","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,27]]},"article-number":"908144"}}