Host Cell–Induced Components of the Sulfate Assimilation Pathway Are Major Protective Antigens of Mycobacterium tuberculosis

Pinto, Rachel; Leotta, Lisa; Shanahan, Erin R.; West, Nicholas P.; Leyh, Thomas S.; Britton, Warwick J.; Triccas, James A.

doi:10.1093/infdis/jis751

Cited by 11 publications

(12 citation statements)

References 39 publications

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“…Sulfur assimilation is critical for M. tuberculosis survival and components of the sulfate assimilation pathway are highly expressed under conditions of sulfur limitation and within macrophages, the principal host cell for M. tuberculosis during infection. 13 , 14 Furthermore, transposon mutagenesis studies showed that genes of this pathway, including cysD , are essential for M. tuberculosis viability. 15 The upregulation of cysD within host cells, coupled with the requirement for sulfate assimilation during chronic M. tuberculosis infection, 16 suggested that expression of CysD may be modified in the host during chronic M. tuberculosis infection.…”

Section: Resultsmentioning

confidence: 99%

“… 13 Although SAP members are non-secreted, the proteins were recognised during the course of M. tuberculosis infection in mice and humans, and were protective against low-dose aerosol challenge in mice. 14 Importantly, the SAP antigens are highly expressed during hypoxia and starvation, suggesting that they may be induced during the latent phase of the bacilli. 13 , 14 In this report, SAP components were identified as highly expressed during chronic M. tuberculosis in mice.…”

Section: Introductionmentioning

confidence: 99%

“… 14 Importantly, the SAP antigens are highly expressed during hypoxia and starvation, suggesting that they may be induced during the latent phase of the bacilli. 13 , 14 In this report, SAP components were identified as highly expressed during chronic M. tuberculosis in mice. A fusion protein vaccine incorporating SAP antigens (CysVac2) was protective in pre- and post-exposure models of TB and could boost the protection afforded by prior BCG vaccination.…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice

et al. 2016

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Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet current control strategies, including the existing BCG vaccine, have had little impact on disease control. The tubercle bacillus modifies protein expression to adapt to chronic infection of the host, and this can potentially be exploited to develop novel therapeutics. We identified the gene encoding the first step of the Mycobacterium tuberculosis sulphur assimilation pathway, cysD, as highly induced during chronic infection in the mouse lung, suggesting therapies based on CysD could be used to target infection. Vaccination with the composite vaccine CysVac2, a fusion of CysD and the immunogenic Ag85B of M. tuberculosis, resulted in the generation of multifunctional CD4+ T cells (interferon (IFN)-γ+TNF+IL-2+IL-17+) in the lung both pre- and post-aerosol challenge with M. tuberculosis. CysVac2 conferred significant protection against pulmonary M. tuberculosis challenge and was particularly effective at controlling late-stage infection, a property not shared by BCG. CysVac2 delivered as a booster following BCG vaccination afforded greater protection against M. tuberculosis challenge than BCG alone. The antigenic components of CysVac2 were conserved amongst M. tuberculosis strains, and protective efficacy afforded by CysVac2 was observed across varying murine MHC haplotypes. Strikingly, administration of CysVac2 to mice previously infected with M. tuberculosis reduced bacterial load and immunopathology in the lung compared with BCG-vaccinated mice. These results indicate that CysVac2 warrants further investigation to assess its potential to control pulmonary TB in humans.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice

et al. 2016

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“…In this direction, Pinto et al . showed that vaccination with ATP sulfurylase conferred significant protection against murine TB and boosted BCG-induced protective immunity in the lung [98] thereby demonstrating that components of sulfate assimilation pathway are promising candidates for inclusion in new vaccines to control TB in humans.…”

Section: Sulfate Import and Activationmentioning

confidence: 99%

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

Paritala¹,

Carroll²

2013

IDDT

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The identification of new antibacterial targets is urgently needed to address multidrug resistant and latent tuberculosis infection. Sulfur metabolic pathways are essential for survival and the expression of virulence in many pathogenic bacteria, including Mycobacterium tuberculosis. In addition, microbial sulfur metabolic pathways are largely absent in humans and therefore, represent unique targets for therapeutic intervention. In this review, we summarize our current understanding of the enzymes associated with the production of sulfated and reduced sulfur-containing metabolites in Mycobacteria. Small molecule inhibitors of these catalysts represent valuable chemical tools that can be used to investigate the role of sulfur metabolism throughout the Mycobacterial lifecycle and may also represent new leads for drug development. In this light, we also summarize recent progress made in the development of inhibitors of sulfur metabolism enzymes.

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“…7 and Supplementary Dataset 3 ). These TRIM27-interacting proteins were mainly involved in the metabolism (such as AtpC, HisG and FabG) 33 34 35 , stress reaction (such as Rv2026c) and intercellular survival (such as LpcC, PtpA, CysK1 and Pks16) 36 37 of Mtb. As expected, Mtb PtpA was among the secreted proteins showing the strongest interaction with TRIM27 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The ubiquitin ligase TRIM27 functions as a host restriction factor antagonized by Mycobacterium tuberculosis PtpA during mycobacterial infection

Wang

Teng

et al. 2016

Sci Rep

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Macrophage-mediated innate immune responses play crucial roles in host defense against pathogens. Recent years have seen an explosion of host proteins that act as restriction factors blocking viral replication in infected cells. However, the essential factors restricting Mycobacterium tuberculosis (Mtb) and their regulatory roles during mycobacterial infection remain largely unknown. We previously reported that Mtb tyrosine phosphatase PtpA, a secreted effector protein required for intracellular survival of Mtb, inhibits innate immunity by co-opting the host ubiquitin system. Here, we identified a new PtpA-interacting host protein TRIM27, which is reported to possess a conserved RING domain and usually acts as an E3 ubiquitin ligase that interferes with various cellular processes. We further demonstrated that TRIM27 restricts survival of mycobacteria in macrophages by promoting innate immune responses and cell apoptosis. Interestingly, Mtb PtpA could antagonize TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis through competitively binding to the RING domain of TRIM27. TRIM27 probably works as a potential restriction factor for Mtb and its function is counteracted by Mtb effector proteins such as PtpA. Our study suggests a potential tuberculosis treatment via targeting of the TRIM27-PtpA interfaces.

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Host Cell–Induced Components of the Sulfate Assimilation Pathway Are Major Protective Antigens of Mycobacterium tuberculosis

Cited by 11 publications

References 39 publications

Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice

Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice

New Targets and Inhibitors of Mycobacterial Sulfur Metabolism

The ubiquitin ligase TRIM27 functions as a host restriction factor antagonized by Mycobacterium tuberculosis PtpA during mycobacterial infection

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