title: Broad adaptive immune responses to M. tuberculosis antigens precede TST conversion in tuberculosis exposed household contacts in a TB-endemic setting.
abstract: BACKGROUND
  The identification of Mycobacterium-tuberculosis (Mtb) infected individuals remains a challenge due to an insufficient understanding of immune responses detected with the current diagnostic tests for latent tuberculosis i.e. the tuberculin skin test (TST) or IFN-γ release assays (IGRAs) and an inability to distinguish infection stages with current immunologic assays. Further classification based on markers other than IFN-γ may help to define markers of early Mtb infection.
  
  
  METHODS
  We assessed the TST status of Mtb-exposed household contacts at baseline and at 6 months. Contacts were classified into those with initial positive TST (TST+); those with baseline negative TST but TST conversion at 6 months (TST converters, TSTC) and those with persistently negative TST (PTST-). We assessed their short- and long-term immune responses to PPD and ESAT-6/CFP-10 (EC) via IFN-γ ELISPOT and a multiplex cytokine array in relation to TST status and compared them to those of TB cases to identify immune profiles associated with a spectrum of infection stages.
  
  
  RESULTS
  After 1 and 6 days stimulation with EC, 12 cytokines (IFN-γ, IL-2, IP-10, TNF-α, IL-13, IL-17, IL-10, GMCSF, MIP-1β, MCP-3, IL-2RA and IL-1A) were not different in TSTC compared to TST+ suggesting that robust adaptive Mtb-specific immune responses precede TST conversion. Stratifying contacts by baseline IFN-γ ELISPOT to EC in combination with TST results revealed that IP-10 and IL-17 were highest in the group of TST converters with positive baseline ELISPOT, suggesting they might be markers for recent infection.
  
  
  CONCLUSIONS
  We describe a detailed analysis of Mtb-specific biomarker profiles in exposed household contacts in a TB endemic area that provides insights into the dynamic immune responses to Mtb infection and may help to identify biomarkers for 'at-risk' populations beyond TST and IGRA.
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Ulrike K
authors.initials: UK
authors.lastname: Buchwald
authors.affiliation: Disease Control and Elimination Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Ifedayo M O
authors.initials: IM
authors.lastname: Adetifa
authors.affiliation: Medical Research Council Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Bottomley
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Owiafe
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Simon
authors.initials: S
authors.lastname: Donkor
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Adama L
authors.initials: AL
authors.lastname: Bojang
authors.affiliation: Vaccinology Theme, Medical Research Council Unit, Banjul, The Gambia.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Sutherland
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D002478:Cells, Cultured; D016358:Contact Tracing; D019353:Endemic Diseases; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification*; D014374:Tuberculin Test; D014376:Tuberculosis / Q000175:diagnosis* / Q000453:epidemiology* / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D007371:Interferon-gamma