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5. Accelerating Early Antituberculosis Drug Discovery by Creating Mycobacterial Indicator Strains That Predict Mode of Action

Author

Boot, Maikel, primary, Commandeur, Susanna, additional, Subudhi, Amit K., additional, Bahira, Meriem, additional, Smith, Trever C., additional, Abdallah, Abdallah M., additional, van Gemert, Mae, additional, Lelièvre, Joël, additional, Ballell, Lluís, additional, Aldridge, Bree B., additional, Pain, Arnab, additional, Speer, Alexander, additional, and Bitter, Wilbert, additional more...

Published
2018
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6. Accelerating early antituberculosis drug discovery by creating mycobacterial indicator strains that predict mode of action

Author

Boot, Maikel, Commandeur, Susanna, Subudhi, Amit K., Bahira, Meriem, Smith, Trever C., Abdallah, Abdallah M., van Gemert, Mae, Lelièvre, Joël, Ballell, Lluís, Aldridge, Bree B., Pain, Arnab, Speer, Alexander, Bitter, Wilbert, Boot, Maikel, Commandeur, Susanna, Subudhi, Amit K., Bahira, Meriem, Smith, Trever C., Abdallah, Abdallah M., van Gemert, Mae, Lelièvre, Joël, Ballell, Lluís, Aldridge, Bree B., Pain, Arnab, Speer, Alexander, and Bitter, Wilbert more...

Abstract

Due to the rise of drug-resistant forms of tuberculosis, there is an urgent need for novel antibiotics to effectively combat these cases and shorten treatment regimens. Recently, drug screens using whole-cell analyses have been shown to be successful. However, current high-throughput screens focus mostly on stricto sensu life/death screening that give little qualitative information. In doing so, promising compound scaffolds or nonoptimized compounds that fail to reach inhibitory concentrations are missed. To accelerate early tuberculosis (TB) drug discovery, we performed RNA sequencing on Mycobacterium tuberculosis and Mycobacterium marinum to map the stress responses that follow upon exposure to subinhibitory concentrations of antibiotics with known targets, ciprofloxacin, ethambutol, isoniazid, streptomycin, and rifampin. The resulting data set comprises the first overview of transcriptional stress responses of mycobacteria to different antibiotics. We show that antibiotics can be distinguished based on their specific transcriptional stress fingerprint. Notably, this fingerprint was more distinctive in M. marinum. We decided to use this to our advantage and continue with this model organism. A selection of diverse antibiotic stress genes was used to construct stress reporters. In total, three functional reporters were constructed to respond to DNA damage, cell wall damage, and ribosomal inhibition. Subsequently, these reporter strains were used to screen a small anti-TB compound library to predict the mode of action. In doing so, we identified the putative modes of action for three novel compounds, which confirms the utility of our approach. more...

Published
2018
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8. New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

Author

Coppola, Mariateresa, van Meijgaarden, Krista E., Franken, Kees L. M. C., Commandeur, Susanna, Dolganov, Gregory, Kramnik, Igor, Schoolnik, Gary K., Comas, Inaki, Lund, Ole, Prins, Corine, van den Eeden, Susan J. F., Korsvold, Gro E., Oftung, Fredrik, Geluk, Annemieke, Ottenhoff, Tom H. M., Coppola, Mariateresa, van Meijgaarden, Krista E., Franken, Kees L. M. C., Commandeur, Susanna, Dolganov, Gregory, Kramnik, Igor, Schoolnik, Gary K., Comas, Inaki, Lund, Ole, Prins, Corine, van den Eeden, Susan J. F., Korsvold, Gro E., Oftung, Fredrik, Geluk, Annemieke, and Ottenhoff, Tom H. M. more...

Abstract

New strategies are needed to develop better tools to control TB, including identification of novel antigens for vaccination. Such Mtb antigens must be expressed during Mtb infection in the major target organ, the lung, and must be capable of eliciting human immune responses. Using genome-wide transcriptomics of Mtb infected lungs we developed data sets and methods to identify IVE-TB (in-vivo expressed Mtb) antigens expressed in the lung. Quantitative expression analysis of 2,068 Mtb genes from the predicted first operons identified the most upregulated IVE-TB genes during in-vivo pulmonary infection. By further analysing high-level conservation among whole-genome sequenced Mtb-complex strains (n = 219) and algorithms predicting HLA-class-Ia and II presented epitopes, we selected the most promising IVE-TB candidate antigens. Several of these were recognized by T-cells from in-vitro Mtb-PPD and ESAT6/CFP10-positive donors by proliferation and multi-cytokine production. This was validated in an independent cohort of latently Mtb-infected individuals. Significant T-cell responses were observed in the absence of IFN-gamma-production. Collectively, the results underscore the power of our novel antigen discovery approach in identifying Mtb antigens, including those that induce unconventional T-cell responses, which may provide important novel tools for TB vaccination and biomarker profiling. Our generic approach is applicable to other infectious diseases. more...

Published
2016

9. New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

Author

Coppola, Mariateresa, primary, van Meijgaarden, Krista E., additional, Franken, Kees L. M. C., additional, Commandeur, Susanna, additional, Dolganov, Gregory, additional, Kramnik, Igor, additional, Schoolnik, Gary K., additional, Comas, Inaki, additional, Lund, Ole, additional, Prins, Corine, additional, van den Eeden, Susan J. F., additional, Korsvold, Gro E., additional, Oftung, Fredrik, additional, Geluk, Annemieke, additional, and Ottenhoff, Tom H. M., additional more...

Published
2016
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10. Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria

Author

Ates, Louis S., primary, Ummels, Roy, additional, Commandeur, Susanna, additional, van der Weerd, Robert, additional, Sparrius, Marion, additional, Weerdenburg, Eveline, additional, Alber, Marina, additional, Kalscheuer, Rainer, additional, Piersma, Sander R., additional, Abdallah, Abdallah M., additional, Abd El Ghany, Moataz, additional, Abdel-Haleem, Alyaa M., additional, Pain, Arnab, additional, Jiménez, Connie R., additional, Bitter, Wilbert, additional, and Houben, Edith N.G., additional more...

Published
2015
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12. Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method

Author

Commandeur, Susanna, primary, Coppola, Mariateresa, additional, Dijkman, Karin, additional, Friggen, Annemieke H., additional, van Meijgaarden, Krista E., additional, van den Eeden, Susan J. F., additional, Wilson, Louis, additional, van der Ploeg-van Schip, Jolien J., additional, Franken, Kees L. M. C., additional, Geluk, Annemieke, additional, and Ottenhoff, Tom H. M., additional more...

Published
2014
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13. An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection

Author

Commandeur, Susanna, primary, van Meijgaarden, Krista E., additional, Prins, Corine, additional, Pichugin, Alexander V., additional, Dijkman, Karin, additional, van den Eeden, Susan J. F., additional, Friggen, Annemieke H., additional, Franken, Kees L. M. C., additional, Dolganov, Gregory, additional, Kramnik, Igor, additional, Schoolnik, Gary K., additional, Oftung, Fredrik, additional, Korsvold, Gro Ellen, additional, Geluk, Annemieke, additional, and Ottenhoff, Tom H. M., additional more...

Published
2013
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14. Double- and monofunctional CD4+ and CD8+ T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals

Author

Commandeur, Susanna, primary, Lin, May Y., additional, van Meijgaarden, Krista E., additional, Friggen, Annemieke H., additional, Franken, Kees L. M. C., additional, Drijfhout, Jan W., additional, Korsvold, Gro E., additional, Oftung, Fredrik, additional, Geluk, Annemieke, additional, and Ottenhoff, Tom H. M., additional more...

Published
2011
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15. Identification of Human T-Cell Responses to Mycobacterium tuberculosis Resuscitation-Promoting Factors in Long-Term Latently Infected Individuals

Author

Commandeur, Susanna, primary, van Meijgaarden, Krista E., additional, Lin, May Young, additional, Franken, Kees L. M. C., additional, Friggen, Annemieke H., additional, Drijfhout, Jan Wouter, additional, Oftung, Fredrik, additional, Korsvold, Gro Ellen, additional, Geluk, Annemieke, additional, and Ottenhoff, Tom H. M., additional more...

Published
2011
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16. Enhancing Sensitivity of Detection of Immune Responses to Mycobacterium leprae Peptides in Whole-Blood Assays

Author

Geluk, Annemieke, primary, van der Ploeg-van Schip, Jolien J., additional, van Meijgaarden, Krista E., additional, Commandeur, Susanna, additional, Drijfhout, Jan W., additional, Benckhuijsen, Willemien E., additional, Franken, Kees L. M. C., additional, Naafs, Bernard, additional, and Ottenhoff, Tom H. M., additional more...

Published
2010
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17. Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method.

Author

Commandeur, Susanna, Coppola, Mariateresa, Dijkman, Karin, Friggen, Annemieke H., van Meijgaarden, Krista E., van den Eeden, Susan J. F., Wilson, Louis, van der Ploeg-van Schip, Jolien J., Franken, Kees L. M. C., Geluk, Annemieke, and Ottenhoff, Tom H. M. more...

Subjects
*TUBERCULOSIS mortality, *CD antigens, *T cells, *CLONING, *CAUSES of death, *TUBERCULIN test, *GENE expression
Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death worldwide. A better understanding of the role of CD4+ and CD8+ T cells, which are both important to TB protection, is essential to unravel the mechanisms of protection and to identify the key antigens seen by these T cells. We have recently identified a set of in vivo expressed Mtb genes (IVE-TB) which is expressed during in vivo pulmonary infection in mice, and shown that their encoded antigens are potently recognized by polyclonal T cells from tuberculin skin test-positive, in vitro ESAT-6/CFP10-responsive individuals. Here we have cloned T cells specific for one of these newly identified in vivo expressed Mtb (IVE-TB) antigens, Rv2034. T cells were enriched based on the expression of CD154 (CD40L), which represents a new method for selecting antigen-specific (low frequency) T cells independent of their specific function. An Rv2034-specific CD4+ T-cell clone expressed the Th1 markers T-bet, IFN-γ, TNF-α, IL-2 and the cytotoxicity related markers granzyme B and CD107a as measured by flow cytometry. The clone specifically recognized Rv2034 protein, Rv2034 peptide p81–100 and Mtb lysate. Remarkably, while the recognition of the dominant p81–100 epitope was HLA-DR restricted, the T-cell clone also recognized a neighboring epitope (p88–107) in an HLA-DR- as well as HLA-DQ1-restricted fashion. Importantly, the T-cell clone was able to inhibit Mtb outgrowth from infected monocytes significantly. The characterization of the polyfunctional and Mtb inhibitory T-cell response to IVE-TB Rv2034 at the clonal level provides detailed further insights into the potential of IVE-TB antigens as new vaccine candidate antigens in TB. Our new approach allowed the identification of T-cell subsets that likely play a significant role in controlling Mtb infection, and can be applied to the analysis of T-cell responses in patient populations. [ABSTRACT FROM AUTHOR] more...

Published
2014
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18. INNOVATIVE STRATEGIES TO IDENTIFY M. TUBERCULOSIS ANTIGENS AND EPITOPES USING GENOME-WIDE ANALYSES.

Author

Annemieke Geluk, van Meijgaarden, Krista E., Joosten, Simone A., Commandeur, Susanna, and Ottenhoff, Tom H. M.

Subjects
MYCOBACTERIUM tuberculosis, T cells, IMMUNE response, BIOMARKERS, CELLULAR immunity
Abstract

The article explores on the capability of mycobacterium tuberculosis (MtB) for the activation of human T-cell responses which design for tuberculosis (TB) vaccination strategies. It highlights the importance of immune responses to identify TB-specific biomarker signatures. It also stresses the use of proteins for different infection phases of MtB in human cellular immunity. more...

Published
2014
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19. Double- and monofunctional CD4+ and CD8+ T-cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long-term latently infected individuals.

Author

Commandeur, Susanna, Lin, May Y., van Meijgaarden, Krista E., Friggen, Annemieke H., Franken, Kees L. M. C., Drijfhout, Jan W., Korsvold, Gro E., Oftung, Fredrik, Geluk, Annemieke, and Ottenhoff, Tom H. M. more...

Abstract

More than 2 billion individuals are latently infected with Mycobacterium tuberculosis ( Mtb). Knowledge of the key Mtb antigens and responding T-cell subsets mediating protection against Mtb is critical for developing improved tuberculosis (TB) vaccines. We previously reported that Mtb DosR-regulon-encoded antigens are recognized well by human T cells in association with control of Mtb infection. The characteristics of the responding T-cell subsets, however, remained unidentified. We have therefore studied the cytokine production and memory phenotypes of Mtb DosR-regulon-encoded antigen-specific T cells from individuals who had been infected with Mtb decades ago, yet never developed TB (long-term latent Mtb-infected individuals). Using multi-parameter flow cytometry and intracellular cytokine staining for IFN-γ, TNF-α and IL-2, we found double and single cytokine-producing CD4+ as well as CD8+ T cells to be the most prominent subsets, particularly IFN-γ+ TNF-α+ CD8+ T cells. The majority of these T cells comprised effector memory and effector T cells. Furthermore, CFSE labeling revealed strong CD4+ and CD8+ T-cell proliferative responses induced by several 'immunodominant' Mtb DosR antigens and their specific peptide epitopes. These findings demonstrate the prominent presence of double- and monofunctional CD4+ and CD8+ T-cell responses in naturally protected individuals and support the possibility of designing Mtb DosR antigen-based TB vaccines. [ABSTRACT FROM AUTHOR] more...

Published
2011
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20. Identification of Human T-Cell Responses to Mycobacterium tuberculosisResuscitation-Promoting Factors in Long-Term Latently Infected Individuals

Author

Commandeur, Susanna, van Meijgaarden, Krista E., Lin, May Young, Franken, Kees L. M. C., Friggen, Annemieke H., Drijfhout, Jan Wouter, Oftung, Fredrik, Korsvold, Gro Ellen, Geluk, Annemieke, and Ottenhoff, Tom H. M. more...

Abstract

ABSTRACTThe Mycobacterium bovisBCG vaccine is the only tuberculosis (TB) vaccine available, yet it provides limited protection against pulmonary TB in adults and fails to protect against TB reactivation. We hypothesized that immunity against Mycobacterium tuberculosis“resuscitation-promoting factors” (Rpfs), which are small bacterial proteins that promote proliferation of dormant mycobacteria, may be relevant in the human immune response to M. tuberculosis. In previous unpublished work, we found that Rpfs Rv0867c and Rv2389c induced gamma interferon (IFN-γ) production in the blood of TB patients' healthy household contacts in several different African populations. Here we examine these two dominant Rpf antigens in more detail and define the nature of the responding T-cell subsets. Multiparameter cytokine profiling showed that Rv2389c and, to a lesser extent, Rv0867c were recognized by mycobacterium-responsive healthy Dutch individuals; peptide-scanning revealed several epitopes, including a single immunodominant epitope in Rv2389c. Rv0867c and, to a lesser extent, Rv2389c Rpf-specific T-cell responses were maintained for decades in long-term M. tuberculosisnonprogressors. Prominent Rv0867c-specific double- and single-cytokine-producing CD8+T-cell subset responses were found, including a large population of CD8+effector memory and effector T-cell subsets. We conclude that M. tuberculosisRpf antigens are important targets in the human immune response to M. tuberculosisand represent interesting TB vaccine candidate antigens. more...

Published
2011
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21. Enhancing Sensitivity of Detection of Immune Responses to Mycobacterium lepraePeptides in Whole-Blood Assays

Author

Geluk, Annemieke, van der Ploeg-van Schip, Jolien J., van Meijgaarden, Krista E., Commandeur, Susanna, Drijfhout, Jan W., Benckhuijsen, Willemien E., Franken, Kees L. M. C., Naafs, Bernard, and Ottenhoff, Tom H. M. more...

Abstract

ABSTRACTAlthough worldwide leprosy prevalence has been reduced considerably following multidrug therapy, new case detection rates remain relatively stable, suggesting that transmission of infection still continues. This calls for new efforts, among which is development of assays that can identify subclinical/early-stage Mycobacterium leprae-infected subjects, a likely source of transmission. Areas in which leprosy is endemic often lack sophisticated laboratories, necessitating development of field-friendly immunodiagnostic tests for leprosy, like short-term whole-blood assays (WBA). In classical, peripheral blood mononuclear cell (PBMC)-based gamma interferon (IFN-?) release assays, M. lepraepeptides have been shown to discriminate in a more specific fashion than M. lepraeproteins between M. leprae-exposed contacts and patients as opposed to healthy controls from the same area of endemicity. However, peptides induced significantly lower levels of IFN-? than did proteins, particularly when whole blood was used. Therefore, possibilities of specifically enhancing IFN-? production in response to M. lepraepeptides in 24-h WBA were sought by addition of various cytokines and antibodies or by mannosylation of peptides. In addition, other cytokines and chemokines were analyzed as potential biomarkers in WBA. We found that only interleukin 12 (IL-12), not other costimulants, increased IFN-? production in WBA while maintaining M. lepraepeptide specificity, as evidenced by lack of increase of IFN-? in control samples stimulated with IL-12 alone. The IL-12-induced increase in IFN-? was mainly mediated by CD4+T cells that did not produce IL-2 or tumor necrosis factor (TNF). Mannosylation further allowed the use of 100-fold-less peptide. Although not statistically significantly, macrophage inflammatory protein 1ß (MIP-1ß) and macrophage c protein 1 (MCP-1) levels specific for M. lepraepeptide tended to be increased by IL-12. IP-10 production was also found to be a useful marker of M. lepraepeptide responses, but its production was enhanced by IL-12 nonspecifically. We conclude that IFN-?-based WBA combined with IL-12 represents a more sensitive and robust assay for measuring reactivity to M. lepraepeptides. more...

Published
2010
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