Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent Manner

Chatterjee, Samit; Dwivedi, Ved Prakash; Singh, Yogesh; Siddiqui, Imran; Sharma, Pawan; Kaer, Luc Van; Chattopadhyay, Debprasad; Das, Gobardhan

doi:10.1371/journal.ppat.1002378

Cited by 141 publications

(164 citation statements)

References 56 publications

(98 reference statements)

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“…sis (33,38). One study suggested that the ESAT-6 expressed by the virulent M. tuberculosis H37Rv strain, but not by Mycobacterium bovis BCG, promoted immunity by enhancing Th17 cell responses (39). Activation of naive T cells by pathogen antigens presented by antigen-presenting cells in the presence of various cytokines leads to the generation of T helper cell subsets, such as Th1, Th2, and Th17.…”

Section: Discussionmentioning

confidence: 99%

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Zhang

Hua

et al. 2015

Infect Immun

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bStaphylococcus aureus is a common pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus is resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization against S. aureus have ended in failure. In this study, we investigated two ESAT-6-like proteins secreted by S. aureus, S. aureus EsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not prevent S. aureus infection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1-and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged with S. aureus compared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines against S. aureus infection.

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Section: Discussionmentioning

confidence: 99%

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Zhang

Hua

et al. 2015

Infect Immun

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“…Inconsistencies in previous reports on IL-12 production in cell infection models after mycobacterial infection may be due to the use of different infection models. Silver et al (2009) Chatterjee et al, 2011). In addition, BCG stimulates significantly higher production of IL-6 than M. bovis.…”

Section: Bovis Has a Stronger Ability Than Bcg To Induce Proinflammentioning

confidence: 98%

“…BCG has lost its virulence at the price of the deletion of five DNA regions called regions of difference (RDs) covering 38 ORFs (Seki et al, 2009), of which region of difference 1 (RD1) is the most prominent. Some previous reports have demonstrated that RD1 protein ESAT-6 promotes differentiation of Th17 cells, which contributes to improved protection against M.tb challenge (Chatterjee et al, 2011). On the other hand, Majlessi et al (2005) reported that BCG complemented with RD1 (BCG : : RD1) can recover virulence in immunecompetent mice, as shown by its persistence in vivo, similar to the virulent strain H37Rv.…”

Section: Bovis Has a Stronger Ability Than Bcg To Induce Proinflammentioning

confidence: 99%

Mycobacterium bovis and BCG induce different patterns of cytokine and chemokine production in dendritic cells and differentiation patterns in CD4+ T cells

Zhang

Luo

et al. 2013

Microbiology

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Mycobacterium tuberculosis can infect dendritic cells (DCs), but the molecular mechanism by which these cells contribute to tuberculosis pathogenesis is largely unclear. Using Mycobacterium bovis and the attenuated strain M. bovis BCG as model strains, we analysed cytokine and chemokine secretion in murine DCs infected with M. bovis and BCG at 6, 12 and 24 h post-infection. BCG enhanced production of MCP-1, RANTES, IL-12, TNF-a and IL-6 in DCs, while M. bovis promoted secretion of IL-1b, IL-10 and IL-23. Heat-killed BCG and M. bovis both stimulated cytokine production, but at significantly lower concentrations than corresponding live bacteria. Quantitative RT-PCR and Western blotting indicated that NF-kB regulates production of most cytokines and chemokines. After DCs were infected for 24 h, the culture was used to activate naïve CD4 + T cells. A combination of the supernatant and activated DCs infected with M. bovis gave high expression of foxp3 and IL-10, directing differentiation of naïve CD4 + T cells into regulatory T cells (CD4 + CD25 + Foxp3 + ) more effectively than BCG. Furthermore, M. bovis-infected DC cultures induced CD4 + T cells to express significantly higher levels of IL-17, a Th17-type cytokine, while BCG-infected DC cultures stimulated an apparently higher production of IFN-c, a Th1-type cytokine. In addition, the mycobacteria did not exert a direct effect on the differentiation of CD4 + T cells. These differential cytokine profiles in DCs and CD4 + T cells, and the resultant development of CD4 + T subsets, may be related to the pathogenesis of tuberculosis.

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“…However, none can fully explain the ability of M. tuberculosis to maintain a latent infection in infected humans without overtly activating the innate inflammatory response. For example, the suppressive effects of ESAT-6, a well-known virulence factor, require g quantities in in vitro systems, and some studies have suggested that ESAT-6 can increase inflammatory responses (11,30,33). One limitation of these studies is a system amenable to high-level protein expression in infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibition occurs following a direct binding of ESAT-6 to Toll-like receptor 2 (TLR2), which subsequently antagonizes TLR2-, TLR4-, and TLR9-mediated re-lease of inflammatory cytokines (33). However, ESAT-6 has also been reported to enhance cytokine production (11). Moreover, ESAT-6 has additional proposed functions, including a lysin and an inflammasome activator (10,17,22,30).…”

mentioning

confidence: 99%

Mycobacterial Shuttle Vectors Designed for High-Level Protein Expression in Infected Macrophages

Eitson

Medeiros

Hoover

et al. 2012

Appl Environ Microbiol

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ABSTRACTMycobacterial shuttle vectors contain dual origins of replication for growth in bothEscherichia coliand mycobacteria. One such vector, pSUM36, was re-engineered for high-level protein expression in diverse bacterial species. The modified vector (pSUM-kan-MCS2) enabled green fluorescent protein expression inE. coli,Mycobacterium smegmatis, andM. aviumat levels up to 50-fold higher than that detected with the parental vector, which was originally developed with alacZα promoter. This high-level fluorescent protein expression allowed easy visualization ofM. smegmatisandM. aviumin infected macrophages. TheM. tuberculosisgeneesat-6was cloned in place of the green fluorescence protein gene (gfp) to determine the impact of ESAT-6 on the innate inflammatory response. The modified vector (pSUM-kan-MCS2) yielded high levels of ESAT-6 expression inM. smegmatis. The ability of ESAT-6 to suppress innate inflammatory pathways was assayed with a novel macrophage reporter cell line, designed with an interleukin-6 (IL-6) promoter-driven GFP cassette. This stable cell line fluoresces in response to diverse mycobacterial strains and stimuli, such as lipopolysaccharide.M. smegmatisclones expressing high levels of ESAT-6 failed to attenuate IL-6-driven GFP expression. Pure ESAT-6, produced inE. coli, was insufficient to suppress a strong inflammatory response elicited byM. smegmatisor lipopolysaccharide, with ESAT-6 itself directly activating the IL-6 pathway. In summary, a pSUM-protein expression vector and a mammalian IL-6 reporter cell line provide new tools for understanding the pathogenic mechanisms deployed by various mycobacterial species.

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Early Secreted Antigen ESAT-6 of Mycobacterium tuberculosis Promotes Protective T Helper 17 Cell Responses in a Toll-Like Receptor-2-dependent Manner

Cited by 141 publications

References 56 publications

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Mycobacterium bovis and BCG induce different patterns of cytokine and chemokine production in dendritic cells and differentiation patterns in CD4+ T cells

Mycobacterial Shuttle Vectors Designed for High-Level Protein Expression in Infected Macrophages

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