title: Interleukin 1-Beta (IL-1β) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients.
abstract: BACKGROUND
  Tuberculosis (TB) remains a major cause of global morbidity and mortality, especially in the context of HIV coinfection because immunity is not completely restored following antiretroviral therapy (ART). The identification of immune correlates of risk for TB disease could help in the design of host-directed therapies and clinical management. This study aimed to identify innate immune correlates of TB recurrence in HIV+ ART-treated individuals with a history of previous successful TB treatment.
  
  
  METHODS
  Twelve participants with a recurrent episode of TB (cases) were matched for age, sex, time on ART, pre-ART CD4 count with 12 participants who did not develop recurrent TB in 60 months of follow-up (controls). Cryopreserved peripheral blood mononuclear cells from time-points before TB recurrence were stimulated with ligands for Toll-like receptors (TLR) including TLR-2, TLR-4, and TLR-7/8. Multicolor flow cytometry and intracellular cytokine staining were used to detect IL-1β, TNF-α, IL-12, and IP10 responses from monocytes and myeloid dendritic cells (mDCs).
  
  
  RESULTS
  Elevated production of IL-1β from monocytes following TLR-2, TLR-4, and TLR-7/8 stimulation was associated with reduced odds of TB recurrence. In contrast, production of IL-1β from both monocytes and mDCs following Bacillus Calmette-Guérin (BCG) stimulation was associated with increased odds of TB recurrence (risk of recurrence increased by 30% in monocytes and 42% in mDCs, respectively).
  
  
  CONCLUSIONS
  Production of IL-1β by innate immune cells following TLR and BCG stimulations correlated with differential TB recurrence outcomes in ART-treated patients and highlights differences in host response to TB.
authors.affiliation: *HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; †Centre for the AIDS Programme of Research in South Africa, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; ‡Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA; §MRC HIV-TB Pathogenesis and Treatment Research Unit, CAPRISA; ‖Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; ¶KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; #Max Planck Institute for Infection Biology, Berlin, Germany; and **Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Thobakgale
authors.forename: Kewreshini
authors.initials: K
authors.lastname: Naidoo
authors.forename: Lyle R
authors.initials: LR
authors.lastname: McKinnon
authors.forename: Lise
authors.initials: L
authors.lastname: Werner
authors.forename: Natasha
authors.initials: N
authors.lastname: Samsunder
authors.forename: Salim Abdool
authors.initials: SA
authors.lastname: Karim
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndungʼu
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Kogieleum
authors.initials: K
authors.lastname: Naidoo
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000032:analysis; D053583:Interleukin-1beta / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D051193:Toll-Like Receptors / Q000378:metabolism; D014376:Tuberculosis / Q000453:epidemiology* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D053583:Interleukin-1beta; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha