Browsing by Author "Thiel, Bonnie"

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    Genetic and Shared Environmental Influences on Interferon-g Production in Response to Mycobacterium tuberculosis Antigens in a Ugandan Population
    (The American Society of Tropical Medicine and Hygiene, 2010) Tao, Li; Zalwango, Sarah; Chervenak, Keith; Thiel, Bonnie; Malone, LaShaunda L.; Feiyou, Qiu; Mayanja-Kizza, Harriet; Boom, Henry; Stein, Catherine M.
    Interferon-g (IFN-g) is a key cytokine in the immune response to Mycobacterium tuberculosis (Mtb). Many studies established IFN-g responses are influenced by host genetics, however differed widely by the study design and heritability estimation method. We estimated heritability of IFN-g responses to Mtb culture filtrate (CF), ESAT-6, and Antigen 85B (Ag85B) in 1,104 Ugandans from a household contact study. Our method separately evaluates shared environmental and genetic variance, therefore heritability estimates were not upwardly biased, ranging from 11.6% for Ag85B to 22.9% for CF. Subset analyses of individuals with latent Mtb infection or without human immunodeficiency virus infection yielded higher heritability estimates, suggesting 10–30% of variation in IFN-g is caused by a shared environment. Immunosuppression does not negate the role of genetics on IFN-g response. These estimates are remarkably close to those reported for components of the innate immune response. These findings have implications for the interpretation of IFN-g response assays and vaccine studies.
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    Resistance and Susceptibility to Mycobacterium tuberculosis Infection and Disease in Tuberculosis Households in Kampala, Uganda
    (Oxford University Press, 2017) Stein, Catherine M.; Zalwango, Sarah; Malone, LaShaunda L.; Thiel, Bonnie; Mupere, Ezekiel; Nsereko, Mary; Okware, Brenda; Kisingo, Hussein; Lancioni, Christina L.; Bark, Charles M.; Whalen, Christopher C.; Joloba, Moses L.; Boom, W. Henry; Mayanja-Kizza, Harriet
    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002–2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.
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    Tuberculin Skin Test Reversion following Isoniazid Preventive Therapy Reflects Diversity of Immune Response to Primary Mycobacterium tuberculosis Infection
    (Katalin Andrea Wilkinson, 2014) Johnson, Denise F.; Malone, LaShaunda L.; Zalwango, Sarah; Oketcho, Joy Mukisa; Chervenak, Keith A.; Thiel, Bonnie; Mayanja-Kizza, Harriet; Stein, Catherine M.; Boom, Henry W.; Lancioni, Christina L.
    Rationale: Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial. Objectives: To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-c) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion. Methods: Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-c responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT. Results: Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-c responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-c responses to Ag85B and wMtb compared to enrollment (p = 0.001, p,0.001, respectively), while there were no significant changes among reverters. Conclusions: TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-c production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.