Human T-cell responses to 25 novel antigens encoded by genes of the dormancy regulon of Mycobacterium tuberculosis

Leyten, Eliane M. S.; Lin, Min; Franken, Kees L. M. C.; Friggen, Annemieke H.; Prins, Corine; Meijgaarden, Krista E. van; Voskuil, Martin I.; Weldingh, Karin; Andersen, Peter; Schoolnik, Gary K.; Arend, Sandra M.; Ottenhoff, Tom H. M.; Klein, Michél R.

doi:10.1016/j.micinf.2006.03.018

Cited by 247 publications

(270 citation statements)

References 32 publications

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“…In this context, it is noteworthy that other studies also have reported reactivity to MTB-encoded antigens in HCs and NTM-infected/exposed individuals that is hypothesized to be as a result of exposure to NTMs (7,8,31). Furthermore, NTM exposure may explain the higher baseline reactivity to PPD that was found in MTB-naive young adults as compared with children (32).…”

Section: Discussionmentioning

confidence: 87%

See 1 more Smart Citation

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Arlehamn

Paul

Mele

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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A previous unbiased genome-wide analysis of CD4 Mycobacterium tuberculosis (MTB) recognition using peripheral blood mononuclear cells from individuals with latent MTB infection (LTBI) or nonexposed healthy controls (HCs) revealed that certain MTB sequences were unexpectedly recognized by HCs. In the present study, it was found that, based on their pattern of reactivity, epitopes could be divided into LTBI-specific, mixed reactivity, and HC-specific categories. This pattern corresponded to sequence conservation in nontuberculous mycobacteria (NTMs), suggesting environmental exposure as an underlying cause of differential reactivity. LTBI-specific epitopes were found to be hyperconserved, as previously reported, whereas the opposite was true for NTM conserved epitopes, suggesting that intragenus conservation also influences host pathogen adaptation. The biological relevance of this observation was demonstrated further by several observations. First, the T cells elicited by MTB/NTM cross-reactive epitopes in HCs were found mainly in a CCR6 + CXCR3 + memory subset, similar to findings in LTBI individuals. Thus, both MTB and NTM appear to elicit a phenotypically similar T-cell response. Second, T cells reactive to MTB/NTMconserved epitopes responded to naturally processed epitopes from MTB and NTMs, whereas T cells reactive to MTB-specific epitopes responded only to MTB. Third, cross-reactivity could be translated to antigen recognition. Several MTB candidate vaccine antigens were cross-reactive, but others were MTB-specific. Finally, NTM-specific epitopes that elicit T cells that recognize NTMs but not MTB were identified. These epitopes can be used to characterize T-cell responses to NTMs, eliminating the confounding factor of MTB cross-recognition and providing insights into vaccine design and evaluation.tuberculosis | T-cell epitope | NTM | epitope conservation | T-cell subset

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Section: Discussionmentioning

confidence: 87%

“…For example, a population in Malawi with no history or scar evidence of prior bCG vaccination or MTB infection showed responsiveness to a variety of mycobacterial antigens and purified protein derivative (PPD) from different NTMs (5,6). In addition, non-MTB-infected and non-bCG-vaccinated individuals respond to MTB-encoded antigens, MTB lysate, and PPD (7,8).…”

mentioning

confidence: 99%

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Arlehamn

Paul

Mele

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We have studied MCP-2 and found a lower sensitivity of 71% for active TB at 97% specificity in healthy controls, but no significant added effect by combination with either IP-10 or IFN-g [52]. In a subsequent eval uation in HIV-infected patients with confirmed TB, we observed significant lower sensitivity of MCP-2 compared with IFN-g and IP-10, and found no added effect by combination Tweaking of the incubation step, for example by increasing incubation temperature [49], prolonging the incubation period [23,92,93], improving culture conditions with nutrients [201] or addition of proinflammatory cytokines (e.g., IL-12 [85]), blocking of anti-inflammatory cytokines (e.g., IL-10 [49,94]) or adding 'survival' cytokines (e.g., IL-7 [95,96]), have also shown potential for augmentation of the antigen-specific immune response.…”

Section: Hot Topics and Unsolved Questionsmentioning

confidence: 81%

IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions

Rühwald

Aabye

Ravn

2012

Expert Review of Molecular Diagnostics

119

117

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“…DosR regulon antigens were found to be preferentially recognized by T-cell in latent TB patients instead of active TB cases. Immune responses against DosR regulon also exist in latent TB patients, suggestive of partial protection for host to repress the Mtb [Demissie et al, 2006;Leyten et al, 2006]. In contrast, T-cell responses against DosR regulon-encoded antigens are very low in BCG-vaccinated mice and humans, possibly emphasizing the importance of unrelenting low dose stimulation from the dormancy pathogen released antigens.…”

Section: Immunological Feature Of Dosr Regulonmentioning

confidence: 99%

“…T-cell can response to three DosR antigens, namely Rv1733c, Rv2029c, Rv2031c, the top 10 most frequently recognized Mtb DosR proteins in Mtb-exposed individuals [Black et al, 2009;Commandeur et al, 2011;Leyten et al, 2006;Schuck et al, 2009]. Strong DosR antigen-specific single and double functional CD4 þ and CD8 þ T-cell responses are detected in LTBI.…”

Section: Immunological Feature Of Dosr Regulonmentioning

confidence: 99%

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

Chen

Deng

et al. 2012

J of Cellular Biochemistry

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c). The underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen.

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Human T-cell responses to 25 novel antigens encoded by genes of the dormancy regulon of Mycobacterium tuberculosis

Cited by 247 publications

References 32 publications

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

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