{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:16:45Z","timestamp":1747196205129,"version":"3.40.5"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>People living with HIV (PLHIV) co-infected with tuberculosis (TB) have a distinct clinical presentation and poorer treatment outcomes compared to HIV-seronegative TB patients. Excluding low CD4 count, innate immune factors associated with TB are not fully elucidated. We, therefore, characterised and compared the expression of IL-6, TNF-\u03b1, IFN-\u03b3, and IL-10 in whole blood of treatment na\u00efve TB patients stimulated with heat-killed Mycobacterium tuberculosis stratified by HIV status and the level of CD4 count.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Results<\/jats:title><jats:p>We recruited 39 HIV seropositive and 31 HIV seronegative TB patients. Median (IQR) age was 35(28\u201342) years and 31(25\u201336) years respectively, and a majority had pulmonary tuberculosis i.e. 38(95%) and 30(97%), respectively. The two groups were significantly different in the distribution of CD4 count, 563 [465\u2013702.5 cells\/mm3] vs 345 [157\u2013483 cell\/mm3] in HIV negative vs HIV positive respectively<jats:italic>p<\/jats:italic>= &lt;0.001. Post stimulation, the expression of IL-6 in HIV negative TB patients was significantly higher than in the HIV positive 16,757366 [8,827\u201323,686 pg\/ml] vs. 9,508 [5,514\u201315,008 pg\/ml], respectively;<jats:italic>p<\/jats:italic>= 0.0360. TNF-\u03b1 and IFN-\u03b3 were highly expressed in HIV negative TB patients compared to the HIV positive though not statistically significant. We only observed higher expression of IL-6 in HIV negative patients in comparison to the HIV positive when stratified by level of CD4 counts as &lt; 500 and \u2265 500 cell\/mm<jats:sup>3<\/jats:sup>for both cohorts. 21,953 [8,990\u201324,206 pg\/ml] vs 9,505 [5,400\u201315,313 pg\/ml],<jats:italic>p<\/jats:italic>value = 0.0585 in patients with CD4 count &lt; 500 cell\/mm<jats:sup>3<\/jats:sup>and 13,168 [7,087\u201322,584 pg\/ml] vs 10,413 [7,397\u201314,806 pg\/ml],<jats:italic>p<\/jats:italic>value = 0.3744 for patients with CD4 count of \u2265 500 cell\/mm3 respectively. We found a positive pairwise correlation between TNF-\u03b1 -alpha and IL-6 in both HIV positive and HIV negative patients, r = 0.61 (95% CI 0.36\u20130.72;<jats:italic>p<\/jats:italic>&lt; 0.0001) and r = 0.48 (95% CI 0.15\u20130.68;<jats:italic>p<\/jats:italic>= 0.005) respectively. The IFN\u03b3\/IL-10 ratio was higher in HIV negative when compared to HIV positive individuals, 0.052 [0.0\u20130.28] vs 0.007 [0\u20130.32] respectively;<jats:italic>p<\/jats:italic>= 0.05759. IL-6 independently reduced the probability of TB\/HIV, Adjusted odds ratio 0.99,<jats:italic>p<\/jats:italic>value 0.007.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Conclusions<\/jats:title><jats:p>This study suggests that HIV seronegative TB patients have a higher pro-inflammatory response to MTB than HIV seropositive TB patients. Further, it also shows that the level of CD4 influences immunomodulation. The findings suggest that the difference in cytokine expression may be responsible for the distinct patterns of TB presentation between HIV positive and HIV negative patient.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0262454","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T19:26:47Z","timestamp":1642102007000},"page":"e0262454","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Immune correlates of Mycobacterium Tuberculosis patients in Zambia stratified by HIV serostatus and level of immunity-a cross-sectional analytical laboratory based study"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6349-1885","authenticated-orcid":true,"given":"Patrick","family":"Lungu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evarist","family":"Njelesani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Sukwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0648-4128","authenticated-orcid":true,"given":"Owen","family":"Ngalamika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sody","family":"Munsaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Kilembe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shabir","family":"Lakhi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Mwaba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"issue":"1","key":"pone.0262454.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-71784-3","article-title":"Mortality and risk of tuberculosis among people living with HIV in whom TB was initially ruled out","volume":"10","author":"JI Garc\u00eda","year":"2020","journal-title":"Sci Rep"},{"key":"pone.0262454.ref002","unstructured":"World Health Organization. Tuberculosis Global Report. 2020. 1\u20132 p."},{"key":"pone.0262454.ref003","unstructured":"World Health Organization. Global tuberculosis report 2018. World Health Organization. http:\/\/www.who.int\/iris\/handle\/10665\/274453. Global Tuberculosis. 2018. 265 p."},{"key":"pone.0262454.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0234878","article-title":"Trends of tuberculosis case detection, mortality and co-infection with HIV in Ghana: A retrospective cohort study","volume":"15","author":"E Osei","year":"2020","journal-title":"PLoS One"},{"issue":"SUPPL. 3","key":"pone.0262454.ref005","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1086\/651495","article-title":"HIV infection-related tuberculosis: Clinical manifestations and treatment","volume":"50","author":"TR Sterling","year":"2010","journal-title":"Clin Infect Dis"},{"key":"pone.0262454.ref006","doi-asserted-by":"crossref","DOI":"10.1155\/2011\/585919","article-title":"HIV-associated tuberculosis.","volume":"2011","author":"K Naidoo","year":"2011","journal-title":"Clin Dev Immunol"},{"issue":"3","key":"pone.0262454.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0193491","article-title":"Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study","volume":"13","author":"M Bastard","year":"2018","journal-title":"PLoS One"},{"key":"pone.0262454.ref008","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.amsu.2020.11.032","article-title":"Impact of HIV status and predictors of successful treatment outcomes among tuberculosis patients: A six-year retrospective cohort study","volume":"60","author":"G Fekadu","year":"2020","journal-title":"Ann Med Surg"},{"issue":"AUG","key":"pone.0262454.ref009","first-page":"1","article-title":"Systemic inflammation and the increased risk of inflamm-aging and age-associated diseases in people living with HIV on long term suppressive antiretroviral therapy","volume":"10","author":"H Babu","year":"2019","journal-title":"Front Immunol"},{"issue":"5","key":"pone.0262454.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.TBTB2-0018-2016","article-title":"Cytokines and Chemokines in Mycobacterium tuberculosis Infection","volume":"4","author":"R Domingo-Gonzalez","year":"2016","journal-title":"Microbiol Spectr"},{"key":"pone.0262454.ref011","article-title":"Th1 and Th17 Cells in Tuberculosis: Protection, Pathology, and Biomarkers","volume":"2015","author":"V. Lyadova I","year":"2015","journal-title":"Mediators Inflamm"},{"issue":"3","key":"pone.0262454.ref012","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/infdis\/jir265","article-title":"Early deaths during tuberculosis treatment are associated with depressed innate responses, bacterial infection, and tuberculosis progression","volume":"204","author":"CJ Waitt","year":"2011","journal-title":"J Infect Dis"},{"issue":"4 SUPPL","key":"pone.0262454.ref013","first-page":"523","article-title":"Reactivation of tuberculosis is associated with a shift from type 1 to type 2 cytokines","volume":"67","author":"AD Howard","year":"1999","journal-title":"Int J Lepr Other Mycobact Dis"},{"issue":"5","key":"pone.0262454.ref014","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1128\/9781555819569.ch2","article-title":"Cytokines and Chemokines in Mycobacterium tuberculosis Infection","volume":"4","author":"R Domingo-Gonzalez","year":"2017","journal-title":"Tuberc Tuber Bacillus"},{"issue":"3","key":"pone.0262454.ref015","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1128\/iai.64.3.913-918.1996","article-title":"Induced Th1 Responses and CTLA-4 Expression","volume":"64","author":"J Gong","year":"1996","journal-title":"Infect Immun"},{"issue":"5","key":"pone.0262454.ref016","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bbamcr.2011.01.034","article-title":"The pro- and anti-inflammatory properties of the cytokine interleukin-6","volume":"1813","author":"J Scheller","year":"2011","journal-title":"Biochim Biophys Acta\u2014Mol Cell Res"},{"issue":"8","key":"pone.0262454.ref017","doi-asserted-by":"crossref","first-page":"5545","DOI":"10.4049\/jimmunol.181.8.5545","article-title":"Interleukin-10 Promotes Mycobacterium tuberculosis Disease Progression in CBA\/J Mice","volume":"181","author":"GL Beamer","year":"2008","journal-title":"J Immunol"},{"issue":"1","key":"pone.0262454.ref018","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3390\/diseases7010002","article-title":"Plasma Levels of Cytokines (IL-10, IFN-\u03b3 and TNF-\u03b1) in Multidrug Resistant Tuberculosis and Drug Responsive Tuberculosis Patients in Ghana","volume":"7","author":"A Basingnaa","year":"2018","journal-title":"Diseases"},{"issue":"6","key":"pone.0262454.ref019","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/1521-4141(200206)32:6<1605::AID-IMMU1605>3.0.CO;2-6","article-title":"Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo","volume":"32","author":"C Lienhardt","year":"2002","journal-title":"Eur J Immunol"},{"key":"pone.0262454.ref020","first-page":"19","article-title":"The two-faced cytokine IL-6 in host defense and diseases","author":"M Narazaki","year":"2018","journal-title":"Int J Mol Sci."},{"key":"pone.0262454.ref021","first-page":"499","article-title":"Sayers TJ OJR of T to interleukins","volume":"56","author":"R Neta","year":"1992","journal-title":"IS"},{"key":"pone.0262454.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/7295390","article-title":"Interferon-Gamma Improves Macrophages Function against M. tuberculosis in Multidrug-Resistant Tuberculosis Patients","volume":"2016","author":"TA Khan","year":"2016","journal-title":"Chemother Res Pract"},{"issue":"2","key":"pone.0262454.ref023","doi-asserted-by":"crossref","first-page":"480 LP","DOI":"10.4049\/jimmunol.144.2.480","article-title":"Infection with HIV is associated with elevated IL-6 levels and production","volume":"144","author":"EC Breen","year":"1990","journal-title":"J Immunol"},{"issue":"1","key":"pone.0262454.ref024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2334-14-125","article-title":"Impact of HIV co-infection on plasma level of cytokines and chemokines of pulmonary tuberculosis patients","volume":"14","author":"A Mihret","year":"2014","journal-title":"BMC Infect Dis"},{"issue":"1","key":"pone.0262454.ref025","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-018-0490-9","article-title":"The effects of highly active antiretroviral therapy on the serum levels of pro-inflammatory and anti-inflammatory cytokines in HIV infected subjects","volume":"25","author":"FN Osuji","year":"2018","journal-title":"J Biomed Sci"},{"issue":"5","key":"pone.0262454.ref026","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/COH.0000000000000094","article-title":"Distinctive features of CD4+ T cell dysfunction in chronic viral infections","volume":"9","author":"A Morou","year":"2014","journal-title":"Curr Opin HIV AIDS"},{"issue":"4","key":"pone.0262454.ref027","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.tube.2007.03.004","article-title":"Interferon\u03b3\/IL10 ratio defines the disease severity in pulmonary and extra pulmonary tuberculosis","volume":"87","author":"B Jamil","year":"2007","journal-title":"Tuberculosis"},{"issue":"10","key":"pone.0262454.ref028","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0046481","article-title":"Altered Ratio of IFN-\u03b3\/IL-10 in Patients with Drug Resistant Mycobacterium tuberculosis and HIV- Tuberculosis Immune Reconstitution Inflammatory Syndrome","volume":"7","author":"KH Skolimowska","year":"2012","journal-title":"PLoS One"},{"issue":"3","key":"pone.0262454.ref029","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1590\/S0074-02761999000300017","article-title":"Comparison between Human Immunodeficiency Virus Positive and Negative Patients with Tuberculosis in Southern Brazil","volume":"94","author":"L Henn","year":"1999","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"pone.0262454.ref030","volume":"2015","author":"PK Ellis","year":"2017","journal-title":"CD4 count and tuberculosis risk in HIV- positive adults not on ART: a systematic review and meta-analysis"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262454","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,22]],"date-time":"2023-01-22T21:58:47Z","timestamp":1674424727000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262454"}},"subtitle":[],"editor":[{"given":"Afsheen","family":"Raza","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262454","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2022,1,13]]}}}