title: Identification of immunological biomarkers which may differentiate latent tuberculosis from exposure to environmental nontuberculous mycobacteria in children.
abstract: A positive gamma interferon (IFN-γ) response to Mycobacterium tuberculosis early secretory antigenic target-6 (ESAT-6)/culture filtrate protein-10 (CFP-10) has been taken to indicate latent tuberculosis (TB) infection, but it may also be due to exposure to environmental nontuberculous mycobacteria in which ESAT-6 homologues are present. We assessed the immune responses to M. tuberculosis ESAT-6 and cross-reactive responses to ESAT-6 homologues of Mycobacterium avium and Mycobacterium kansasii. Archived culture supernatant samples from children at 3 years post-BCG vaccination were tested for cytokine/chemokine responses to M. tuberculosis antigens. Furthermore, the IFN-γ responses to M. tuberculosis antigens were followed up for 40 children at 8 years post-BCG vaccination, and 15 TB patients were recruited as a control group for the M. tuberculosis ESAT-6 response in Malawi. IFN-γ enzyme-linked immunosorbent assays (ELISAs) on supernatants from diluted whole-blood assays, IFN-γ enzyme-linked immunosorbent spot (ELISpot) assays, QuantiFERON TB Gold-In Tube tests, and multiplex bead assays were performed. More than 45% of the responders to M. tuberculosis ESAT-6 showed IFN-γ responses to M. avium and M. kansasii ESAT-6. In response to M. tuberculosis ESAT-6/CFP-10, interleukin 5 (IL-5), IL-9, IL-13, and IL-17 differentiated the stronger IFN-γ responders to M. tuberculosis ESAT-6 from those who preferentially responded to M. kansasii and M. avium ESAT-6. A cytokine/chemokine signature of IL-5, IL-9, IL-13, and IL-17 was identified as a putative immunological biosignature to differentiate latent TB infection from exposure to M. avium and M. kansasii in Malawian children, indicating that this signature might be particularly informative in areas where both TB and exposure to environmental nontuberculous mycobacteria are endemic.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Yun-Gyoung
authors.initials: YG
authors.lastname: Hur
authors.forename: Amelia C
authors.initials: AC
authors.lastname: Crampin
authors.forename: Christina
authors.initials: C
authors.lastname: Chisambo
authors.forename: James
authors.initials: J
authors.lastname: Kanyika
authors.forename: Rein
authors.initials: R
authors.lastname: Houben
authors.forename: Richard
authors.initials: R
authors.lastname: Ndhlovu
authors.forename: Themba
authors.initials: T
authors.lastname: Mzembe
authors.forename: Maeve K
authors.initials: MK
authors.lastname: Lalor
authors.forename: Jacky
authors.initials: J
authors.lastname: Saul
authors.forename: Keith
authors.initials: K
authors.lastname: Branson
authors.forename: Carolynne
authors.initials: C
authors.lastname: Stanley
authors.forename: Bagrey
authors.initials: B
authors.lastname: Ngwira
authors.forename: Neil
authors.initials: N
authors.lastname: French
authors.forename: Tom H
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.forename: Patricia
authors.initials: P
authors.lastname: Gorak-Stolinska
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D019411:Clinical Laboratory Techniques / Q000379:methods*; D016207:Cytokines / Q000097:blood*; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D006801:Humans; D007118:Immunoassay / Q000379:methods; D007223:Infant; D007231:Infant, Newborn; D055985:Latent Tuberculosis / Q000175:diagnosis*; D008295:Malawi; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous / Q000175:diagnosis*; D009162:Mycobacterium avium / Q000276:immunology; D019909:Mycobacterium kansasii / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines