Browsing by Author "Gideon, Hannah Priyadarshini"

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    Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines
    (Public Library of Science, 2010) Gideon, Hannah Priyadarshini; Wilkinson, Katalin Andrea; Rustad, Tige R; Oni, Tolu; Guio, Heinner; Kozak, Robert Andrew; Sherman, David R; Meintjes, Graeme; Behr, Marcel A; Vordermeier, Hans Martin
    Author Summary Mycobacterium tuberculosis (the cause of tuberculosis) can persist for many years in humans without causing disease but has the potential to reactivate. One of the conditions the bacterium must survive in these circumstances is hypoxia. In order to do so, the bacterium uses a characteristic set of genes that help alter its metabolism. It follows that the products of such genes may encode protein antigens that can be recognized by the immune response. We therefore analyzed gene response patterns of tuberculosis subject to prolonged hypoxia as a guide to the discovery of new antigens that might be useful as vaccines or diagnostic agents. Amongst the genes most strongly increased by low oxygen levels, one was identified (known as Rv1986) that is missing from most strains of the tuberculosis vaccine Mycobacterium bovis BCG. When we analyzed human immune responses to this protein in tuberculosis infected people our experiments showed it was particularly well recognized by cells that produce a chemical messenger (cytokine) called interleukin-2. Interleukin-2 is important for long-term immunological memory. The BCG vaccine is only partially effective and our experiments therefore suggest one of the reasons could be that an important immunological target is missing from many strains. Further evaluation of BCG strains in which Rv1986 is present or absent is therefore warranted in the hope that this might improve the efficacy of existing or new tuberculosis vaccines.
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    Impairment of IFN-gamma response to synthetic peptides of mycobacterium tuberculosis in a 7-day whole blood assay
    (Public Library of Science, 2013) Gideon, Hannah Priyadarshini; Hamilton, Melissa Shea; Wood, Kathryn; Pepper, Dominique; Oni, Tolu; Seldon, Ronnett; Banwell, Claire; Langford, Paul R; Wilkinson, Robert J; Wilkinson, Katalin A
    Studies on Mycobacterium tuberculosis (MTB) antigens are of interest in order to improve vaccine efficacy and to define biomarkers for diagnosis and treatment monitoring. The methodologies used for these investigations differ greatly between laboratories and discordant results are common. The IFN-gamma response to two well characterized MTB antigens ESAT-6 and CFP-10, in the form of recombinant proteins and synthetic peptides, was evaluated in HIV-1 uninfected persons in both long-term (7 day) and 24 hour, commercially available QuantiFERON TB Gold in Tube (QFT-GIT), whole blood assays. Our findings showed differences in the IFN-gamma response between 24 hour and 7 day cultures, with recombinant proteins inducing a significantly higher response than the peptide pools in 7 day whole blood assays. The activity of peptides and recombinant proteins did not differ in 24 hour whole blood or peripheral blood mononuclear cell (PBMC) based assays, nor in the ELISpot assay. Further analysis by SELDI-TOF mass spectrometry showed that the peptides are degraded over the course of 7 days of incubation in whole blood whilst the recombinant proteins remain intact. This study therefore demonstrates that screening antigenic candidates as synthetic peptides in long-term whole blood assays may underestimate immunogenicity.
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    Studies on in vitro human T cell reactivity to antigens of mycobacterium tuberculosis
    (2010) Gideon, Hannah Priyadarshini; Wilkinson, Robert J; Wilkinson, Katalin
    Studies on Mycobacterium tuberculosis (MTB) antigens are important to improve immunodiagnostics and vaccine efficacy. A novel genome based strategy for antigen discovery is to relate what is highly expressed by bacilli in vivo or in vitro, to what is recognized by human T cells as antigens. As hypoxia is a relevant stimulus that MTB encounters in vivo, whole genome based transcriptional profiles of M. tuberculosis subject to prolonged hypoxia (described as the Enduring hypoxic response (EHR) were analyzed, to guide the discovery of novel potential anitgens, by a combined bioinformatic and empirical approach and to determine evidence of infection stage specific recognition.