{"doi":"10.1371/journal.pone.0327243","title":"Activation and proliferation profiles of M.tuberculosis specific dual functional CD4+T cells from smear negative pulmonary TB patients","abstract":"BACKGROUND: Tuberculosis is a major public health challenge in the resource-limited endemic setting of sub-Saharan Africa. The diagnostic challenge becomes worse for smear-negative TB cases. Even if efforts for non-sputum-based TB diagnostic and prognostic biomarkers, there was limited data on blood-based immunological biomarkers among smear-negative PTB patients.Therefore, we assessed the phenotypic profile (HLA-DR, CD-38, Ki-67) of M. tuberculosis specific CD4 + T cells expressing dual IFN-γ and TNF-α cytokines from smear negative PTB patients in Addis Ababa, Ethiopia. METHODOLOGY: An institutional-based longitudinal cohort study was conducted in Addis Abeba, Ethiopia, on new smear-negative PTB who were adult and HIV-negative in comparison with multiple comparator groups. A total of 149 (confirmed patients with non-TB respiratory disease -33, smear-negative TB-29, smear-positive TB-34, apparently healthy - 53) study participants was enrolled. The expression level of activation (HLA-DR, CD-38) and proliferation (Ki-67) markers from dual IFN-γ and TNF-α cytokines expressing PPD specific CD4 + T cells were assessed after surface and intracellular cytokine staining. To confirm the presence of M. tuberculosis, MGIT/LJ culture, PCR, and smear microscopy were performed. RESULT: The overall level of HLA-DR and CD-38 expression in smear-negative and positive pulmonary TB patients were substantially higher than that of confirmed non-TB respiratory illness, apparently healthy QFT positive and negative study participants (p-value = 0.0127, p-value < 0.0001, p-value = 0.0043, p-value <0.0001, respectively) before commencing anti TB treatment. Also, among the smear-negative and positive pulmonary TB cohort, the expression of CD-38, HLA-DR, and HLA-DR + CD-38 + expression was reduced in the second month and six-month cohort compared with baseline data (p-value= < 0.0001, p-value = 0.00365, p -value = 0.0001, respectively). CONCLUSION: In this study, we found the diagnostic and prognostic potential of activation markers, particularly CD-38, in smear-negative PTB patients from dual M. tuberculosis-specific IFN-γ + TNF-α+ cytokine producing CD4 + T cells in both the presumed ex vivo and antigen-specific stimulation assays.","journal":"PLoS ONE","year":2025,"id":554053,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9319,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":947917,"name":"Adane Mihret","orcid":"0000-0003-3183-4772","position":1,"is_corresponding":false},{"id":309102,"name":"Tamrat Abebe","orcid":"0000-0002-6100-9303","position":2,"is_corresponding":false},{"id":930183,"name":"Daniel Mussa","orcid":null,"position":3,"is_corresponding":false},{"id":963115,"name":"Sebsib Neway","orcid":"0000-0002-2033-5874","position":4,"is_corresponding":false},{"id":8685,"name":"J. Ernst","orcid":"0000-0001-9951-6207","position":5,"is_corresponding":false},{"id":280891,"name":"Jyothi Rengarajan","orcid":"0000-0003-1241-4705","position":6,"is_corresponding":false},{"id":487247,"name":"Liya Wassie","orcid":"0000-0002-5494-5275","position":7,"is_corresponding":false},{"id":754386,"name":"Rawleigh Howe","orcid":"0000-0002-4001-5456","position":8,"is_corresponding":false},{"id":947916,"name":"Ahmed Esmael","orcid":"0000-0002-0310-0280","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:54:45.872391Z","pmid":"40901996","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}