Browsing by Author "Stein, Catherine M."
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Item 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.Item Genome Scan of M. tuberculosis Infection and Disease in Ugandans(PLoS ONE, 2018) Stein, Catherine M.; Zalwango, Sarah; Malone, LaShaunda L.; Won1, Sungho; Mayanja- Kizza, Harriet; Mugerwa, Roy D.; Leontiev, Dmitry V.; Thompson, Cheryl L.; Cartier, Kevin C.; Elston, Robert C.; Iyengar, Sudha K.; Boom, Henry; Whalen, Christopher C.Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFa) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p,1023) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal a = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFa p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFa p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.Item Heritability Analysis of Cytokines as Intermediate Phenotypes of Tuberculosis(The Journal of infectious diseases, 2003) Stein, Catherine M.; Guwatudde, David; Nakakeeto, Margaret; Peters, Pierre; Elston, Robert C.; Tiwari, Hemant K.; Mugerwa, Roy; Whalen, Christopher C.Numerous studies have provided support for genetic susceptibility to tuberculosis (TB); however, heterogeneity in disease expression has hampered previous genetic studies. The purpose of this work was to investigate possible intermediate phenotypes for TB. A set of cytokine profiles, including antigen-stimulated whole-blood assays for interferon (IFN)–g, tumor necrosis factor (TNF)–a, transforming growth factor (TGF)–b, and the ratio of IFN to TNF, were analyzed in 177 pedigrees from a community in Uganda with a high prevalence of TB. The heritability of these variables was estimated after adjustment for covariates, and TNF-a, in particular, had an estimated heritability of 68%. A principal component analysis of IFN-g, TNF-a, and TGF-b reflected the immunologic model of TB. In this analysis, the first component explained 138% of the variation in the data. This analysis illustrates the value of such intermediate phenotypes in mapping susceptibility loci for TB and demonstrates that this area deserves further research.Item Innate and Adaptive Immune Responses during Acute M. tuberculosis Infection in Adult Household Contacts in Kampala, Uganda(The American journal of tropical medicine and hygiene, 2011) Mahan, C. Scott; Zalwango, Sarah; Thiel, Bonnie A.; Malone, LaShaunda L.; Chervenak, Keith A.; Baseke, Joy; Dobbs, Dennis; Stein, Catherine M.; Mayanja, Harriet; Joloba, Moses; Whalen, Christopher C.; Boom, W. HenryContacts of active pulmonary tuberculosis (TB) patients are at risk for Mycobacterium tuberculosis (MTB) infection. Because most infections are controlled, studies during MTB infection provide insight into protective immunity. We compared immune responses of adult household contacts that did and did not convert the tuberculin skin test (TST). Innate and adaptive immune responses were measured by whole blood assay. Responses of TST converters (TSTC) were compared with persistently TST negative contacts (PTST–) and contacts who were TST+ at baseline (TST+). TLR-2, TLR-4, and IFN-gR responses to IFN-g did not differ between the groups, nor did gd T cell responses. T cell responses to MTB antigens differed markedly among TSTC, PTST–, and TST+ contacts. Thus, no differences in innate responses were found among the three household contact groups. However, adaptive T cell responses to MTB antigens did differ before and during MTB infection among PTST–, TSTC, and TST+ contacts.Item Interaction between host genes and Mycobacterium tuberculosis lineage can affect tuberculosis severity: Evidence for coevolution?(PLoS genetics, 2020) McHenry, Michael L.; Bartlett, Jacquelaine; Igo, Robert P.; Wampande, Eddie M.; Mayanja-Kizza, Harriet; Hall, Noemi B.; Tishkoff, Sarah A.; Stein, Catherine M.Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.Item Lean Tissue Mass Wasting is Associated With Increased Risk of Mortality Among Women With Pulmonary Tuberculosis in Urban Uganda(Elsevier Inc., 2012) Mupere, Ezekiel; Malone, Lashaunda; Zalwango, Sarah; Chiunda, Allan; Okwera, Alphonse; Parraga, Isabel; Stein, Catherine M.; Tisch, Daniel J.; Mugerwa, Roy; Boom, W. Henry; Mayanja, Harriet; Whalen, Christopher C.OBJECTIVES: We assessed the impact of wasting on survival in patients with tuberculosis by using a precise height-normalized lean tissue mass index (LMI) estimated by bioelectrical impedance analysis and body mass index (BMI). METHODS: In a retrospective cohort study, 747 adult pulmonary patients with tuberculosis who were screened for HIV and nutritional status were followed for survival. RESULTS: Of 747 patients, 310 had baseline wasting by BMI (kg/m2) and 103 by LMI (kg/m2). Total deaths were 105. Among men with reduced BMI, risk of death was 70% greater (hazard ratio [HR] 1.7, 95% confidence interval [95% CI] 1.03–2.81) than in men with normal BMI. Survival did not differ by LMI among men (HR 1.1; 95% CI 0.5–2.9). In women, both the BMI and LMI were associated with survival. Among women with reduced BMI, risk of death was 80% greater (HR 1.8; 95% CI 0.9–3.5) than in women with normal BMI; risk of death was 5-fold greater (HR 5.0; 95% CI 1.6–15.9) for women with low LMI compared with women with normal LMI. CONCLUSIONS: Wasting assessed by reduced BMI is associated with an increased risk for death among both men and women whereas reduced LMI is among women with tuberculosis.Item Linkage and association analysis of candidate genes for TB and TNFa cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes(Springer, 2007) Stein, Catherine M.; Zalwango, Sarah; Chiunda, Allan B.; Millard, Christopher; Leontiev, Dmitry V.; Horvath, Amanda L.; Cartier, Kevin C.; Chervenak, Keith; Boom, W. Henry; Elston, Robert C.; Mugerwa, Roy D.; Whalen, Christopher C.; Iyengar, Sudha K.Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-a (TNFa) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFa regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFa receptor 1 (TNFR1) genes were linked and associated to both TB and TNFa. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits.Item Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda(Clinical Infectious Diseases, 2019) Stein, Catherine M.; Nsereko, Mary; Malone, LaShaunda L.; Okware, Brenda; Kisingo, Hussein; Nalukwago, Sophie; Chervenak, Keith; Mayanja-Kizza, Harriet; Hawn, Thomas R.; Boom, W. HenryResistance to latent Mycobacterium tuberculosis (M.tb) infection, identified by persistently negative tuberculin skin tests (TST) and interferon-gamma release assays (IGRA), after close contact with pulmonary tuberculosis (TB) patients has not been extensively characterized. Stability of this “resistance” beyond 2 years from exposure is unknown. Methods. 407 of 657 eligible human immunodeficiency virus (HIV)-negative adults from a TB household contact study with persistently negative TST (PTST−) or with stable latent M.tb infection (LTBI) were retraced 9.5 years (standard deviation = 3.2) later. Asymptomatic retraced contacts underwent 3 IGRAs and follow-up TST, and their M.tb infection status classified as definite/ possible/probable. Results. Among PTST− with a definite classification, 82.7% were concordantly TST−/ quantiferon-TB Gold− (QFT−), and 16.3% converted to TST+/QFT+ LTBI. Among original LTBI contacts, 83.6% remained LTBI, and 3.9% reverted their TST and were QFT−. Although TST and QFT concordance was high (κ = 0.78), 1.0% of PTST and 12.5% of original LTBI contacts could not be classified due to discordant TST and QFT results. Epidemiological variables did not differ between retraced PTST− and LTBI contacts. Conclusion. Resistance to LTBI, defined by repeatedly negative TST and IGRA, in adults who have had close contact with pulmonary TB patients living in TB-endemic areas, is a stable outcome of M.tb exposure. Repeated longitudinal measurements with 2 different immune assays and extended follow-up provide enhanced discriminatory power to identify this resister phenotype and avoid misclassification. Resisters may use immune mechanisms to control aerosolized M.tb that differ from those used by persons who develop “classic” LTBI.Item 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, HarrietTuberculosis (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.Item Resistance to TST/IGRA conversion in Uganda: Heritability and Genome-Wide 2 Association Study(EBioMedicine, 2021) McHenry, Michael L.; Benchek, Penelope; Malone, LaShaunda; Nsereko, Mary; Mayanja-Kizza, Harriet; Boom, W. Henry; Williams, Scott M.; Hawn, Thomas R.; Stein, Catherine M.Pulmonary tuberculosis (TB) is one of the most deadly pathogens on earth. However, the majority of people have resistance to active disease. Further, some individuals, termed resisters (RSTRs), do not develop traditional latent tuberculosis (LTBI). The RSTR phenotype is important for understanding pathogenesis and preventing TB. The host genetic underpinnings of RSTR are largely understudied. Methods: In a cohort of 908 Ugandan subjects with genome-wide data on single nucleotide polymorphisms, we assessed the heritability of the RSTR phenotype and other TB phenotypes using restricted maximum likelihood estimation (REML). We then used a subset of 263 RSTR and LTBI subjects with high quality phenotyping and long-term follow-up to identify DNA variants genome-wide associated with the RSTR phenotype relative to LTBI subjects in a case- control GWAS design, and annotated and enriched these variants to better understand their role in TB pathogenesis. Results: The heritability of the TB outcomes was very high, at 55% for TB vs. LTBI and 50.4% for RSTR vs. LTBI among HIV- subjects, controlling for age and sex. We identified 27 loci associated with the RSTR phenotype (P<5e-05) and our annotation and enrichment analyses suggest an important regulatory role for many of them. Interpretation: The heritability results show that the genetic contribution to variation in TB outcomes is very high and our GWAS results highlight variants that may play an important role in resistance to infection as well as TB pathogenesis as a whole.Item 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.Item Tuberculosis case finding in first-degree relative contacts not living with index tuberculosis cases in Kampala, Uganda(Dove Medical Press Limited,, 2015) Chheng, Phalkun; Nsereko, Mary; Malone, LaShaunda L.; Okware, Brenda; Zalwango, Sarah; Joloba, Moses; Boom, Henry W.; Mupere, Ezekiel; Stein, Catherine M.To assess the prevalence of pulmonary tuberculosis among first-degree relative (FDR) contacts not living with tuberculosis (TB) cases. Methods: A cross-sectional analysis of household contacts living with an index TB case and FDR contacts living outside of households in Kampala, Uganda, is presented.Results: A total of 177 contacts (52 FDRs and 125 index household contacts) of 31 TB cases were examined. Compared with index household contacts, FDR contacts were older, more likely to be TB symptomatic (50% vs 33%), had a higher percentage of abnormal chest X-rays (19% vs 11%), sputum smear positive (15% vs 5%), and many similar epidemiologic risk factors, including HIV infection (13% vs 10%). Contact groups had similar pulmonary tuberculosis prevalence: 9.6% in FDR vs 10.4% in index household contacts and similar Mycobacterium tuberculosis infection: 62% in FDR vs 61% in index households.Conclusion: TB is common among FDR contacts. High TB prevalence justifies targeting FDRs during household contact investigations. Combining TB active-case finding among FDR contacts with household contact investigation in low-income setting is feasible. This should be part of national TB control program strategies for increasing TB case-detection rates and reducing community TB transmission and death.Item Wasting among Uganda men with pulmonary tuberculosis is associated with linear regain in lean tissue mass during and after treatment in contrast to women with wasting who regain fat tissue mass: prospective cohort study(Bio med central, 2014) Malone, LaShaunda; Zalwango, Sarah; Okwera, Alphonse; Nsereko, Mary; Tisch, Daniel J; Parraga, Isabel M; Stein, Catherine M.; Mugerwa, Roy; Boom, Henry W.; Mayanja, Harriet K; Whalen, Christopher C; Mupere, EzekielBackground: Nutritional changes during and after tuberculosis treatment have not been well described. We therefore determined the effect of wasting on rate of mean change in lean tissue and fat mass as measured by bioelectrical impedance analysis (BIA), and mean change in body mass index (BMI) during and after tuberculosis treatment. Methods: In a prospective cohort study of 717 adult patients, BMI and height-normalized indices of lean tissue (LMI) and fat mass (FMI) as measured by BIA were assessed at baseline, 3, 12, and 24 months. Results: Men with wasting at baseline regained LMI at a greater rate than FMI (4.55 kg/m2 (95% confidence interval (CI): 1.26, 7.83 versus 3.16 (95% CI: 0.80, 5.52)) per month, respectively during initial tuberculosis therapy. In contrast, women with wasting regained FMI at greater rate than LMI (3.55 kg/m2 (95% CI: 0.40, 6.70) versus 2.07 (95% CI: -0.74, 4.88)), respectively. Men with wasting regained BMI at a rate of 6.45 kg/m2 (95% CI: 3.02, 9.87) in the first three months whereas women, had a rate of 3.30 kg/m2 (95% CI: -0.11, 6.72). There were minimal changes in body composition after month 3 and during months 12 to 24. Conclusion: Wasted tuberculosis patients regain weight with treatment but the type of gain differs by gender and patients may remain underweight after the initial phase of treatmentItem Whole Blood Interferon-Gamma Responses to Mycobacterium tuberculosis Antigens in Young Household Contacts of Persons with Tuberculosis in Uganda(Plos one, 2008) Lewinsohn, Deborah A.; Zalwango, Sarah.; Stein, Catherine M.; Mayanja-Kizza, Harriet.; Okwera, Alphonse.; Boom, Henry W.; Mugerwa, Roy D.; Whalen, Christopher C.Background: Due to immunologic immaturity, IFN-c-producing T cell responses may be decreased in young children compared to adults, thus we hypothesized that IFN-c responses to mycobacterial antigens in household contacts exposed to Mycobacterium tuberculosis (Mtb) would be impaired in young children relative to adults. The objective of this study was to compare whole blood IFN-c production in response to mycobacterial antigens between children and adults in Uganda. Methodology/Principal Findings: We studied household contacts of persons with culture-positive pulmonary tuberculosis (TB) enrolled in a cohort study conducted in Kampala, Uganda. Whole blood IFN-c production in response to Mtb culturefiltrate antigens was measured by ELISA and compared between infants (,2 years old, n = 80), young children (2 ,5 years old, n = 216), older children (5 ,15 years old, n = 443) and adults ($15 years old, n = 528). We evaluated the relationship between IFN-c responses and the tuberculin skin test (TST), and between IFN-c responses and epidemiologic factors that reflect exposure to Mtb, and the effect of prior BCG vaccination on IFN-c responses. Young household contacts demonstrated robust IFN-c responses comparable to those of adults that were associated with TST and known risk factors for infection. There was no effect of prior BCG immunization on the IFN-c response. Conclusions/Significance: Young children in a TB endemic setting can mount robust IFN-c responses generally comparable to those of adults, and as in adults, these responses correlated with the TST and known epidemiologic risk factors forMtb infection.