{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:56:25Z","timestamp":1793642185337,"version":"4.5.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011094","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Interferon-\u03b3 (IFN-\u03b3) is a key cytokine inducing protective immune responses during tuberculosis (TB) infection. Helminth-induced immune responses may affect IFN-\u03b3 production by T cells, although its connection with disease severity and immune recovery during treatment is unexplored. We investigated the species-specific effect of helminths on the IFN-\u03b3 production by T cells in relation to disease severity during active and latent TB infection (LTBI).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>In this study, 69 active pulmonary TB patients (PTB), 28 with LTBI and 66 healthy controls were included. Active TB was diagnosed using GenXpert MTB\/RIF while QuantiFERON test (QFT) was used for the screening of healthy community controls (CCs) and for the diagnosis of LTBI. Helminth infection was identified by routine diagnosis whereas clinical disease severity was evaluated by the TB score. Intracellular IFN-\u03b3 production of T cells in stimulated peripheral blood mononuclear cells (PBMCs) was analyzed by flow cytometry using TB antigens (PPD), the polyclonal T cell activator staphylococcal enterotoxin B (SEB), or medium as unstimulated control.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Helminth infected CCs and LTBI subjects showed a significant reduction of IFN-\u03b3<jats:sup>+<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T cells by PPD-stimulation compared to non-helminth infected control groups. The significant reduction in the frequency of IFN-\u03b3<jats:sup>+<\/jats:sup> T cells in both latent and active PTB patients following SEB stimulation was mostly attributed to <jats:italic>Schistosoma mansoni<\/jats:italic> infection, whereas <jats:italic>Ascaris lumbricoides<\/jats:italic>, <jats:italic>Schistosoma mansoni<\/jats:italic>, and hookworm infection contributed equally in CCs. Following anti-helminthic and anti-TB treatment for 2 months, the frequency of IFN-\u03b3<jats:sup>+<\/jats:sup> CD4 T cells in helminth coinfected PTB was restored to levels of helminth negative PTB before treatment. Helminth coinfected PTB patients with an intermediate and severe clinical course had reduced capacity for production of IFN-\u03b3<jats:sup>+<\/jats:sup> T cells compared to the corresponding non-helminth infected PTB.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>We found a reduction in IFN-\u03b3 producing T cells by helminth coinfection which was restored following anti-helminthic treatment. This reduction was helminth species-dependent in an exploratory sub-analysis and correlated to increased disease severity.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0011094","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T19:04:38Z","timestamp":1674241478000},"page":"e0011094","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Helminth species-specific effects on IFN-\u03b3 producing T cells during active and latent tuberculosis"],"prefix":"10.1371","volume":"17","author":[{"given":"Amare","family":"Kiflie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gezahegn","family":"Bewket","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fitsumbrhan","family":"Tajebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebba","family":"Abate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Sch\u04e7n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-8175","authenticated-orcid":true,"given":"Robert","family":"Blomgran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,20]]},"reference":[{"key":"pntd.0011094.ref001","article-title":"Global Tuberculosis Report 2020\u2013Reflections on the Global TB burden, treatment and prevention efforts.","author":"J Chakaya","year":"2021","journal-title":"International Journal of Infectious Diseases."},{"key":"pntd.0011094.ref002","first-page":"54","article-title":"The global prevalence of latent tuberculosis: a systematic review and meta-analysis","author":"A Cohen","year":"2019","journal-title":"European Respiratory Journal"},{"issue":"10117","key":"pntd.0011094.ref003","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/S0140-6736(17)31930-X","article-title":"Soil-transmitted helminth infections","volume":"391","author":"PM Jourdan","year":"2018","journal-title":"The Lancet"},{"issue":"1","key":"pntd.0011094.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12879-020-05237-7","article-title":"Intestinal parasites co-infection among tuberculosis patients in Ethiopia: a systematic review and meta-analysis.","volume":"20","author":"A Alemu","year":"2020","journal-title":"BMC infectious diseases"},{"issue":"8","key":"pntd.0011094.ref005","doi-asserted-by":"crossref","first-page":"e0003994","DOI":"10.1371\/journal.pntd.0003994","article-title":"Asymptomatic helminth infection in active tuberculosis is associated with increased regulatory and Th-2 responses and a lower sputum smear positivity.","volume":"9","author":"E Abate","year":"2015","journal-title":"PLoS neglected tropical diseases."},{"issue":"9","key":"pntd.0011094.ref006","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.it.2016.07.005","article-title":"Helminth-tuberculosis co-infection: an immunologic perspective","volume":"37","author":"S Babu","year":"2016","journal-title":"Trends in immunology"},{"issue":"6","key":"pntd.0011094.ref007","doi-asserted-by":"crossref","first-page":"e0008069","DOI":"10.1371\/journal.pntd.0008069","article-title":"Interactions between helminths and tuberculosis infections: Implications for tuberculosis diagnosis and vaccination in Africa.","volume":"14","author":"SI Cadmus","year":"2020","journal-title":"PLoS neglected tropical diseases"},{"issue":"9","key":"pntd.0011094.ref008","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nri1183","article-title":"Immune regulation by helminth parasites: cellular and molecular mechanisms","volume":"3","author":"RM Maizels","year":"2003","journal-title":"Nature Reviews Immunology"},{"issue":"11","key":"pntd.0011094.ref009","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1084\/jem.20110919","article-title":"Regulation of neutrophils by interferon-\u03b3 limits lung inflammation during tuberculosis infection","volume":"208","author":"B Nandi","year":"2011","journal-title":"Journal of Experimental Medicine"},{"issue":"1","key":"pntd.0011094.ref010","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1158\/2326-6066.CIR-14-0098","article-title":"Cytotoxic T lymphocytes block tumor growth both by lytic activity and IFN\u03b3-dependent cell-cycle arrest","volume":"3","author":"H Matsushita","year":"2015","journal-title":"Cancer immunology research"},{"issue":"10","key":"pntd.0011094.ref011","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/ni.2702","article-title":"Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory \u03b3\u03b4 T cell subsets","volume":"14","author":"N Schmolka","year":"2013","journal-title":"Nature immunology"},{"issue":"4","key":"pntd.0011094.ref012","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.4049\/jimmunol.1402099","article-title":"Activation-specific metabolic requirements for NK Cell IFN-\u03b3 production","volume":"194","author":"MP Keppel","year":"2015","journal-title":"The Journal of Immunology"},{"issue":"1","key":"pntd.0011094.ref013","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/ni.2474","article-title":"Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome\u2013dependent processing of IL-1\u03b2","volume":"14","author":"BB Mishra","year":"2013","journal-title":"Nature immunology"},{"issue":"1","key":"pntd.0011094.ref014","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4049\/jimmunol.1200061","article-title":"IFN-\u03b3 from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection","volume":"190","author":"AM Green","year":"2013","journal-title":"The Journal of Immunology"},{"issue":"6","key":"pntd.0011094.ref015","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1084\/jem.178.6.2243","article-title":"Disseminated tuberculosis in interferon gamma gene-disrupted mice","volume":"178","author":"AM Cooper","year":"1993","journal-title":"Journal of Experimental Medicine"},{"key":"pntd.0011094.ref016","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-1-4615-0059-9_24","article-title":"Human deficiencies in type-1 cytokine receptors reveal the essential role of type-1 cytokines in immunity to intracellular bacteria.","author":"TH Ottenhoff","year":"2003","journal-title":"Tropical Diseases."},{"key":"pntd.0011094.ref017","first-page":"2019","article-title":"Genetic polymorphisms of IFNG and IFNGR1 with latent tuberculosis infection","author":"S Wu","year":"2019","journal-title":"Disease Markers"},{"key":"pntd.0011094.ref018","doi-asserted-by":"crossref","first-page":"146392","DOI":"10.1016\/j.gene.2022.146392","article-title":"Association of single nucleotide polymorphisms of interferon-\u03b3 with pulmonary tuberculosis in population of Himachal Pradesh, India.","volume":"823","author":"NS Dhiman","year":"2022","journal-title":"Gene"},{"issue":"3","key":"pntd.0011094.ref019","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1086\/513769","article-title":"Clinical correlates of interferon \u03b3 production in patients with tuberculosis","volume":"25","author":"A Sodhi","year":"1997","journal-title":"Clinical infectious diseases"},{"issue":"6","key":"pntd.0011094.ref020","doi-asserted-by":"crossref","first-page":"e65492","DOI":"10.1371\/journal.pone.0065492","article-title":"T cell activation and proinflammatory cytokine production in clinically cured tuberculosis are time-dependent and accompanied by upregulation of IL-10.","volume":"8","author":"MVd Silva","year":"2013","journal-title":"PLoS One."},{"key":"pntd.0011094.ref021","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/978-1-4939-1489-0_3","author":"N du Plessis","year":"2014","journal-title":"Helminth-M. tb co-infection. How helminths alter immunity to infection"},{"key":"pntd.0011094.ref022","doi-asserted-by":"crossref","first-page":"102126","DOI":"10.1016\/j.tube.2021.102126","article-title":"Differential effects of asymptomatic Ascaris lumbricoides, Schistosoma mansoni or hook worm infection on the frequency and TGF-beta-producing capacity of regulatory T cells during active tuberculosis","volume":"131","author":"A Kiflie","year":"2021","journal-title":"Tuberculosis"},{"issue":"2","key":"pntd.0011094.ref023","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/00365540701558698","article-title":"TBscore: Signs and symptoms from tuberculosis patients in a low-resource setting have predictive value and may be used to assess clinical course.","volume":"40","author":"C Wejse","year":"2008","journal-title":"Scandinavian journal of infectious diseases"},{"issue":"2","key":"pntd.0011094.ref024","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3390\/tropicalmed5020093","article-title":"Diagnostic techniques of soil-transmitted helminths: Impact on control measures","volume":"5","author":"M Mbong Ngwese","year":"2020","journal-title":"Tropical Medicine and Infectious Disease"},{"issue":"4","key":"pntd.0011094.ref025","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ymeth.2005.12.004","article-title":"Intracellular cytokine staining for the characterization and quantitation of antigen-specific T lymphocyte responses","volume":"38","author":"M-C Gauduin","year":"2006","journal-title":"Methods"},{"issue":"4","key":"pntd.0011094.ref026","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/j.1365-3156.2006.01578.x","article-title":"Are intestinal helminths risk factors for developing active tuberculosis?","volume":"11","author":"D Elias","year":"2006","journal-title":"Tropical Medicine & International Health."},{"key":"pntd.0011094.ref027","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1590\/S0100-879X1998000100024","article-title":"Cytokines as determinants of resistance and pathology in human Schistosoma mansoni infection","volume":"31","author":"R Correa-Oliveira","year":"1998","journal-title":"Brazilian journal of medical and biological research"},{"issue":"11\u201312","key":"pntd.0011094.ref028","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1046\/j.1365-3024.2002.00600.x","article-title":"Cellular responses and cytokine profiles in Ascaris lumbricoides and Trichuris trichiura infected patients","volume":"24","author":"SM Geiger","year":"2002","journal-title":"Parasite immunology"},{"key":"pntd.0011094.ref029","doi-asserted-by":"crossref","DOI":"10.1155\/2010\/428593","article-title":"Immunity against helminths: interactions with the host and the intercurrent infections.","volume":"2010","author":"E Moreau","year":"2010","journal-title":"Journal of Biomedicine and Biotechnology"},{"issue":"8","key":"pntd.0011094.ref030","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1034\/j.1398-9995.2000.00477.x","article-title":"Prenatal immune priming with helminth infections: parasite-specific cellular reactivity and Th1 and Th2 cytokine responses in neonates","volume":"55","author":"D Pit","year":"2000","journal-title":"Allergy"},{"issue":"1","key":"pntd.0011094.ref031","doi-asserted-by":"crossref","first-page":"124","DOI":"10.4049\/jimmunol.1800101","article-title":"Schistosomiasis induces persistent DNA methylation and tuberculosis-specific immune changes","volume":"201","author":"AR DiNardo","year":"2018","journal-title":"The Journal of Immunology"},{"issue":"3","key":"pntd.0011094.ref032","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1002\/eji.201545843","article-title":"Mycobacterium tuberculosis-specific CD4+ T-cell response is increased, and Treg cells decreased, in anthelmintic-treated patients with latent TB","volume":"46","author":"F Toulza","year":"2016","journal-title":"European journal of immunology"},{"issue":"6","key":"pntd.0011094.ref033","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.tube.2015.09.009","article-title":"Modulation of pro-and anti-inflammatory cytokines in active and latent tuberculosis by coexistent Strongyloides stercoralis infection","volume":"95","author":"PJ George","year":"2015","journal-title":"Tuberculosis"},{"issue":"9","key":"pntd.0011094.ref034","doi-asserted-by":"crossref","first-page":"e1004375","DOI":"10.1371\/journal.ppat.1004375","article-title":"Helminth infections coincident with active pulmonary tuberculosis inhibit mono-and multifunctional CD4+ and CD8+ T cell responses in a process dependent on IL-10.","volume":"10","author":"PJ George","year":"2014","journal-title":"PLoS pathogens."},{"issue":"3","key":"pntd.0011094.ref035","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/infdis\/jiw156","article-title":"Schistosome soluble egg antigen decreases Mycobacterium tuberculosis\u2013specific CD4+ T-cell effector function with concomitant arrest of macrophage phago-lysosome maturation","volume":"214","author":"AR DiNardo","year":"2016","journal-title":"The Journal of infectious diseases"},{"issue":"3","key":"pntd.0011094.ref036","doi-asserted-by":"crossref","first-page":"e0009194","DOI":"10.1371\/journal.pntd.0009194","article-title":"Helminth species specific expansion and increased TNF-alpha production of non-classical monocytes during active tuberculosis","volume":"15","author":"G Bewket","year":"2021","journal-title":"PLoS Neglected Tropical Diseases"},{"issue":"2\u20133","key":"pntd.0011094.ref037","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ijpara.2014.09.006","article-title":"Effects of albendazole on the clinical outcome and immunological responses in helminth co-infected tuberculosis patients: a double blind randomised clinical trial","volume":"45","author":"E Abate","year":"2015","journal-title":"International journal for parasitology"},{"issue":"4","key":"pntd.0011094.ref038","doi-asserted-by":"crossref","first-page":"e00973","DOI":"10.1128\/IAI.00973-16","article-title":"Anthelmintic therapy modifies the systemic and mycobacterial antigen-stimulated cytokine profile in helminth-latent Mycobacterium tuberculosis coinfection","volume":"85","author":"R Anuradha","year":"2017","journal-title":"Infection and immunity"},{"issue":"7","key":"pntd.0011094.ref039","doi-asserted-by":"crossref","first-page":"724","DOI":"10.3390\/biomedicines9070724","article-title":"Increased Th1 Cells with Disease Resolution of Active Pulmonary Tuberculosis in Non-Atopic Patients.","volume":"9","author":"C-Y Lo","year":"2021","journal-title":"Biomedicines"},{"issue":"1","key":"pntd.0011094.ref040","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1365-2249.2006.03247.x","article-title":"Intestinal helminth co-infection has a negative impact on both anti-Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy.","volume":"147","author":"T Resende Co","year":"2007","journal-title":"Clinical & Experimental Immunology."}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0011094","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011094","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T19:12:53Z","timestamp":1675278773000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011094"}},"subtitle":[],"editor":[{"given":"Maria Victoria","family":"Periago","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,20]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011094","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0011094","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,20]]}}}