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  1. Article ; Online: Attrition of T-cell functions and simultaneous upregulation of inhibitory markers correspond with the waning of BCG-induced protection against tuberculosis in mice.

    Subhadra Nandakumar / Sunil Kannanganat / James E Posey / Rama Rao Amara / Suraj B Sable

    PLoS ONE, Vol 9, Iss 11, p e

    2014  Volume 113951

    Abstract: Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal ... ...

    Abstract Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal changes in the magnitude and functional quality of CD4(+) and CD8(+) T-cell response over a period of two years after mucosal or parenteral BCG vaccination with the strength of protection against Mycobacterium tuberculosis in mice. The BCG vaccination-induced CD4(+) and CD8(+) T cells exhibited comparable response kinetics but distinct functional attributes in-terms of IFN-γ, IL-2 and TNF-α co-production and CD62L memory marker expression. Despite a near life-long BCG persistence and the induction of enduring CD4(+) T-cell responses characterized by IFN-γ and/or TNF-α production with comparable protection, the protective efficacy waned regardless of the route of vaccination. The progressive decline in the multifactorial functional abilities of CD4(+) and CD8(+) T cells in-terms of type-1 cytokine production, proliferation and cytolytic potential corresponded with the waning of protection against M. tuberculosis infection. In addition, simultaneous increase in the dysfunctional and terminally-differentiated T cells expressing CTLA-4, KLRG-1 and IL-10 during the contraction phase of BCG-induced response coincided with the loss of protection. Our results question the empirical development of BCG-booster vaccines and emphasize the pursuit of strategies that maintain superior T-cell functional capacity. Furthermore, our results underscore the importance of understanding the comprehensive functional dynamics of antigen-specific T-cell responses in addition to cytokine polyfunctionality in BCG-vaccinated hosts while optimizing novel vaccination strategies against tuberculosis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Statistical Method to Detect Tuberculosis Outbreaks among Endemic Clusters in a Low-Incidence Setting

    Sandy P. Althomsons / Andrew N. Hill / Alexia V. Harrist / Anne Marie France / Krista M. Powell / James E. Posey / Lauren S. Cowan / Thomas R. Navin

    Emerging Infectious Diseases, Vol 24, Iss 3, Pp 573-

    2018  Volume 575

    Abstract: We previously reported use of genotype surveillance data to predict outbreaks among incident tuberculosis clusters. We propose a method to detect possible outbreaks among endemic tuberculosis clusters. We detected 15 possible outbreaks, of which 10 had ... ...

    Abstract We previously reported use of genotype surveillance data to predict outbreaks among incident tuberculosis clusters. We propose a method to detect possible outbreaks among endemic tuberculosis clusters. We detected 15 possible outbreaks, of which 10 had epidemiologic data or whole-genome sequencing results. Eight outbreaks were corroborated.
    Keywords tuberculosis and other mycobacteria ; bacteria ; respiratory infections ; molecular epidemiology ; genotype ; endemic clusters ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Centers for Disease Control and Prevention
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: New insights into fluoroquinolone resistance in Mycobacterium tuberculosis

    Seidu Malik / Melisa Willby / David Sikes / Oleg V Tsodikov / James E Posey

    PLoS ONE, Vol 7, Iss 6, p e

    functional genetic analysis of gyrA and gyrB mutations.

    2012  Volume 39754

    Abstract: Fluoroquinolone antibiotics are among the most potent second-line drugs used for treatment of multidrug-resistant tuberculosis (MDR TB), and resistance to this class of antibiotics is one criterion for defining extensively drug resistant tuberculosis ( ... ...

    Abstract Fluoroquinolone antibiotics are among the most potent second-line drugs used for treatment of multidrug-resistant tuberculosis (MDR TB), and resistance to this class of antibiotics is one criterion for defining extensively drug resistant tuberculosis (XDR TB). Fluoroquinolone resistance in Mycobacterium tuberculosis has been associated with modification of the quinolone resistance determining region (QRDR) of gyrA. Recent studies suggest that amino acid substitutions in gyrB may also play a crucial role in resistance, but functional genetic studies of these mutations in M. tuberculosis are lacking. In this study, we examined twenty six mutations in gyrase genes gyrA (seven) and gyrB (nineteen) to determine the clinical relevance and role of these mutations in fluoroquinolone resistance. Transductants or clinical isolates harboring T80A, T80A+A90G, A90G, G247S and A384V gyrA mutations were susceptible to all fluoroquinolones tested. The A74S mutation conferred low-level resistance to moxifloxacin but susceptibility to ciprofloxacin, levofloxacin and ofloxacin, and the A74S+D94G double mutation conferred cross resistance to all the fluoroquinolones tested. Functional genetic analysis and structural modeling of gyrB suggest that M330I, V340L, R485C, D500A, D533A, A543T, A543V and T546M mutations are not sufficient to confer resistance as determined by agar proportion. Only three mutations, N538D, E540V and R485C+T539N, conferred resistance to all four fluoroquinolones in at least one genetic background. The D500H and D500N mutations conferred resistance only to levofloxacin and ofloxacin while N538K and E540D consistently conferred resistance to moxifloxacin only. Transductants and clinical isolates harboring T539N, T539P or N538T+T546M mutations exhibited low-level resistance to moxifloxacin only but not consistently. These findings indicate that certain mutations in gyrB confer fluoroquinolone resistance, but the level and pattern of resistance varies among the different mutations. The results from this study ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Using Reduced Inoculum Densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to Prevent False-Resistant Results and Improve Accuracy

    Glenn P. Morlock / Frances C. Tyrrell / Dorothy Baynham / Vincent E. Escuyer / Nicole Green / Youngmi Kim / Patricia A. Longley-Olson / Nicole Parrish / Courtney Pennington / Desmond Tan / Brett Austin / James E. Posey

    Tuberculosis Research and Treatment, Vol

    A Multicenter Evaluation

    2017  Volume 2017

    Abstract: The primary platform used for pyrazinamide (PZA) susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson). Since false-resistant results have been associated with the use of this system, we conducted a ... ...

    Abstract The primary platform used for pyrazinamide (PZA) susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson). Since false-resistant results have been associated with the use of this system, we conducted a multicenter evaluation to determine the effect of using a reduced cell density inoculum on the rate of false resistance. Two reduced inoculum densities were compared with that prescribed by the manufacturer (designated as “BD” method). The reduced inoculum methods (designated as “A” and “C”) were identical to the manufacturer’s protocol in all aspects with the exception of the cell density of the inoculum. Twenty genetically and phenotypically characterized M. tuberculosis isolates were tested in duplicate by ten independent laboratories using the three inoculum methods. False-resistant results declined from 21.1% using the standard “BD” method to 5.7% using the intermediate (“A”) inoculum and further declined to 2.8% using the most dilute (“C”) inoculum method. The percentages of the resistant results that were false-resistant declined from 55.2% for the “BD” test to 28.8% and 16.0% for the “A” and “C” tests, respectively. These results represent compelling evidence that the occurrence of false-resistant MGIT PZA susceptibility test results can be mitigated through the use of reduced inoculum densities.
    Keywords Medicine ; R
    Subject code 630
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Ultralong C100 mycolic acids support the assignment of Segniliparus as a new bacterial genus.

    Sunhee Hong / Tan-Yun Cheng / Emilie Layre / Lindsay Sweet / David C Young / James E Posey / W Ray Butler / D Branch Moody

    PLoS ONE, Vol 7, Iss 6, p e

    2012  Volume 39017

    Abstract: Mycolic acid-producing bacteria isolated from the respiratory tract of human and non-human mammals were recently assigned as a distinct genus, Segniliparus, because they diverge from rhodococci and mycobacteria in genetic and chemical features. Using ... ...

    Abstract Mycolic acid-producing bacteria isolated from the respiratory tract of human and non-human mammals were recently assigned as a distinct genus, Segniliparus, because they diverge from rhodococci and mycobacteria in genetic and chemical features. Using high accuracy mass spectrometry, we determined the chemical composition of 65 homologous mycolic acids in two Segniliparus species and separately analyzed the three subclasses to measure relative chain length, number and stereochemistry of unsaturations and cyclopropyl groups within each class. Whereas mycobacterial mycolate subclasses are distinguished from one another by R groups on the meromycolate chain, Segniliparus species synthesize solely non-oxygenated α-mycolates with high levels of cis unsaturation. Unexpectedly Segniliparus α-mycolates diverge into three subclasses based on large differences in carbon chain length with one bacterial culture producing mycolates that range from C58 to C100. Both the overall chain length (C100) and the chain length diversity (C42) are larger than previously seen for mycolic acid-producing organisms and provide direct chemical evidence for assignment of Segniliparus as a distinct genus. Yet, electron microscopy shows that the long and diverse mycolates pack into a typical appearing membrane. Therefore, these new and unexpected extremes of mycolic acid chemical structure raise questions about the modes of mycolic acid packing and folding into a membrane.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Discordance in Mycobacterium tuberculosis Rifampin Susceptibility

    Ameeta S. Kalokhe / Majid Shafiq / James C. Lee / Beverly Metchock / James E. Posey / Susan M. Ray / Albert Anderson / Yun F. Wang / Minh Ly T. Nguyen

    Emerging Infectious Diseases, Vol 18, Iss 3, Pp 538-

    2012  Volume 539

    Keywords multidrug-resistant tuberculosis ; molecular diagnostic testing ; microbial sensitivity tests ; Mycobacterium tuberculosis ; tuberculosis and other mycobacteria ; rifampin susceptibility ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
    Language English
    Publishing date 2012-03-01T00:00:00Z
    Publisher Centers for Disease Control and Prevention
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Cellular immune responses to nine Mycobacterium tuberculosis vaccine candidates following intranasal vaccination.

    Suraj B Sable / Mani Cheruvu / Subhadra Nandakumar / Sunita Sharma / Kakali Bandyopadhyay / Kathryn L Kellar / James E Posey / Bonnie B Plikaytis / Rama Rao Amara / Thomas M Shinnick

    PLoS ONE, Vol 6, Iss 7, p e

    2011  Volume 22718

    Abstract: BACKGROUND: The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. METHODS AND PRINCIPAL FINDINGS: In this study, a ... ...

    Abstract BACKGROUND: The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. METHODS AND PRINCIPAL FINDINGS: In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. CONCLUSION AND SIGNIFICANCE: Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: O-mannosylation of the Mycobacterium tuberculosis adhesin Apa is crucial for T cell antigenicity during infection but is expendable for protection.

    Subhadra Nandakumar / Sunil Kannanganat / Karen M Dobos / Megan Lucas / John S Spencer / Sunan Fang / Melissa A McDonald / Jan Pohl / Kristin Birkness / Venkateswarlu Chamcha / Melissa V Ramirez / Bonnie B Plikaytis / James E Posey / Rama Rao Amara / Suraj B Sable

    PLoS Pathogens, Vol 9, Iss 10, p e

    2013  Volume 1003705

    Abstract: Glycosylation is the most abundant post-translational polypeptide chain modification in nature. Although carbohydrate modification of protein antigens from many microbial pathogens constitutes important components of B cell epitopes, the role in T cell ... ...

    Abstract Glycosylation is the most abundant post-translational polypeptide chain modification in nature. Although carbohydrate modification of protein antigens from many microbial pathogens constitutes important components of B cell epitopes, the role in T cell immunity is not completely understood. Here, using ELISPOT and polychromatic flow cytometry, we show that O-mannosylation of the adhesin, Apa, of Mycobacterium tuberculosis (Mtb) is crucial for its T cell antigenicity in humans and mice after infection. However, subunit vaccination with both mannosylated and non-mannosylated Apa induced a comparable magnitude and quality of T cell response and imparted similar levels of protection against Mtb challenge in mice. Both forms equally improved waning BCG vaccine-induced protection in elderly mice after subunit boosting. Thus, O-mannosylation of Apa is required for antigenicity but appears to be dispensable for its immunogenicity and protective efficacy in mice. These results have implications for the development of subunit vaccines using post-translationally modified proteins such as glycoproteins against infectious diseases like tuberculosis.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Independent large scale duplications in multiple M. tuberculosis lineages overlapping the same genomic region.

    Brian Weiner / James Gomez / Thomas C Victor / Robert M Warren / Alexander Sloutsky / Bonnie B Plikaytis / James E Posey / Paul D van Helden / Nicolass C Gey van Pittius / Michael Koehrsen / Peter Sisk / Christian Stolte / Jared White / Sebastien Gagneux / Bruce Birren / Deborah Hung / Megan Murray / James Galagan

    PLoS ONE, Vol 7, Iss 2, p e

    2012  Volume 26038

    Abstract: Mycobacterium tuberculosis, the causative agent of most human tuberculosis, infects one third of the world's population and kills an estimated 1.7 million people a year. With the world-wide emergence of drug resistance, and the finding of more functional ...

    Abstract Mycobacterium tuberculosis, the causative agent of most human tuberculosis, infects one third of the world's population and kills an estimated 1.7 million people a year. With the world-wide emergence of drug resistance, and the finding of more functional genetic diversity than previously expected, there is a renewed interest in understanding the forces driving genome evolution of this important pathogen. Genetic diversity in M. tuberculosis is dominated by single nucleotide polymorphisms and small scale gene deletion, with little or no evidence for large scale genome rearrangements seen in other bacteria. Recently, a single report described a large scale genome duplication that was suggested to be specific to the Beijing lineage. We report here multiple independent large-scale duplications of the same genomic region of M. tuberculosis detected through whole-genome sequencing. The duplications occur in strains belonging to both M. tuberculosis lineage 2 and 4, and are thus not limited to Beijing strains. The duplications occur in both drug-resistant and drug susceptible strains. The duplicated regions also have substantially different boundaries in different strains, indicating different originating duplication events. We further identify a smaller segmental duplication of a different genomic region of a lab strain of H37Rv. The presence of multiple independent duplications of the same genomic region suggests either instability in this region, a selective advantage conferred by the duplication, or both. The identified duplications suggest that large-scale gene duplication may be more common in M. tuberculosis than previously considered.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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