title: New biomarkers with relevance to leprosy diagnosis applicable in areas hyperendemic for leprosy.
abstract: Leprosy is not eradicable with currently available diagnostics or interventions, as evidenced by its stable incidence. Early diagnosis of Mycobacterium leprae infection should therefore be emphasized in leprosy research. It remains challenging to develop tests based on immunological biomarkers that distinguish individuals controlling bacterial replication from those developing disease. To identify biomarkers for field-applicable diagnostics, we determined cytokines/chemokines induced by M. leprae proteins in blood of leprosy patients and endemic controls (EC) from high leprosy-prevalence areas (Bangladesh, Brazil, Ethiopia) and from South Korea, where leprosy is not endemic anymore. M. leprae-sonicate-induced IFN-γ was similar for all groups, excluding M. leprae/IFN-γ as a diagnostic readout. By contrast, ML2478 and ML0840 induced high IFN-γ concentrations in Bangladeshi EC, which were completely absent for South Korean controls. Importantly, ML2478/IFN-γ could indicate distinct degrees of M. leprae exposure, and thereby the risk of infection and transmission, in different parts of Brazilian and Ethiopian cities. Notwithstanding these discriminatory responses, M. leprae proteins did not distinguish patients from EC in one leprosy-endemic area based on IFN-γ. Analyses of additional cytokines/chemokines showed that M. leprae and ML2478 induced significantly higher concentrations of MCP-1, MIP-1β, and IL-1β in patients compared with EC, whereas IFN-inducible protein-10, like IFN-γ, differed between EC from areas with dissimilar leprosy prevalence. This study identifies M. leprae-unique Ags, particularly ML2478, as biomarker tools to measure M. leprae exposure using IFN-γ or IFN-inducible protein-10, and also shows that MCP-1, MIP-1β, and IL-1β can potentially distinguish pathogenic immune responses from those induced during asymptomatic exposure to M. leprae.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. ageluk@lumc.nl
authors.forename: Annemieke
authors.initials: A
authors.lastname: Geluk
authors.forename: Kidist
authors.initials: K
authors.lastname: Bobosha
authors.forename: Jolien J
authors.initials: JJ
authors.lastname: van der Ploeg-van Schip
authors.forename: John S
authors.initials: JS
authors.lastname: Spencer
authors.forename: Sayera
authors.initials: S
authors.lastname: Banu
authors.forename: Marcia V S B
authors.initials: MV
authors.lastname: Martins
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yonas
authors.initials: Y
authors.lastname: Bekele
authors.forename: Mohammad K M
authors.initials: MK
authors.lastname: Uddin
authors.forename: Sheikh Abdul
authors.initials: SA
authors.lastname: Hadi
authors.forename: Abraham
authors.initials: A
authors.lastname: Aseffa
authors.forename: Maria C V
authors.initials: MC
authors.lastname: Pessolani
authors.forename: Geraldo M B
authors.initials: GM
authors.lastname: Pereira
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology; D001459:Bangladesh / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D001938:Brazil / Q000453:epidemiology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D005002:Ethiopia / Q000453:epidemiology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D007918:Leprosy / Q000175:diagnosis / Q000453:epidemiology* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000276:immunology*; D056910:Republic of Korea / Q000453:epidemiology; D018417:Th1 Cells / Q000276:immunology / Q000382:microbiology; D018418:Th2 Cells / Q000276:immunology / Q000382:microbiology; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; D016207:Cytokines; D007371:Interferon-gamma