Browsing by Author "Chervenak, Keith A."

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    Comprehensive definition of human immunodominant CD8 antigens in tuberculosis
    (NPJ vaccines, 2017) Lewinsohn, Deborah A.; Swarbrick, Gwendolyn M.; Park, Byung; Cansler, Meghan E.; Null, Megan D.; Toren, Katelynne G.; Baseke, Joy; Zalwango, Sarah; Mayanja-Kizza, Harriet; Malone, LaShaunda L.; Nyendak, Melissa; Wu, Guanming; Guinn, Kristi; McWeeney, Shannon; Mori, Tomi; Chervenak, Keith A.; Sherman, David R.; Boom, W. Henry; Lewinsohn, David M.
    Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with Mycobacterium tuberculosis, remains a leading cause of morbidity and mortality worldwide. As CD8+ T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8+ T cell response, an effective tuberculosis vaccine may need to induce CD8+ T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis. Herein, we report the results of the first ever HLA allele independent genome-wide CD8 antigen discovery program. Using CD8+ T cells derived from humans with latent tuberculosis infection or tuberculosis and an interferon-γ ELISPOT assay, we screened a synthetic peptide library representing 10% of the Mycobacterium tuberculosis proteome, selected to be enriched for Mycobacterium tuberculosis antigens. We defined a set of immunodominant CD8 antigens including part or all of 74 Mycobacterium tuberculosis proteins, only 16 of which are previously known CD8 antigens. Immunogenicity was associated with the degree of expression of mRNA and protein. Immunodominant antigens were enriched in cell wall proteins with preferential recognition of Esx protein family members, and within proteins comprising the Mycobacterium tuberculosis secretome. A validation study of immunodominant antigens demonstrated that these antigens were strongly recognized in Mycobacterium tuberculosisinfected individuals from a tuberculosis endemic region in Africa. The tuberculosis vaccine field will likely benefit from this greatly increased known repertoire of CD8 immunodominant antigens and definition of properties of Mycobacterium tuberculosis proteins important for CD8 antigenicity.
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    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. Henry
    Contacts 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.
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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.