Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of<i>Mycobacterium tuberculosis</i>

Zumbo, Antonella; Palucci, Ivana; Cascioferro, Alessandro; Sali, Michela; Ventura, Marcello; D’Alfonso, Pamela; Iantomasi, Raffaella; Sante, Gabriele Di; Ria, Francesco; Sanguinetti, Maurizio; Fadda, Giovanni; Manganelli, Riccardo; Delogu, Giovanni

doi:10.1111/2049-632x.12096

Cited by 38 publications

(39 citation statements)

References 31 publications

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“…The PGRS domain interacts with the TLR2-inducing apoptosis, targets the mitochondria triggering necrosis, and is responsible of the immunomodulatory properties of the entire protein (14, 22, 25). Even though the mentioned characteristics of the PE and PGRS domains have been elucidated, their contribution to the immunogenicity of the complete PE_PGRS33 protein has not been described.…”

Section: Discussionmentioning

confidence: 99%

“…This domain directs the cell wall localization of PE_PGRS33 (21). It has been reported that mutations in the PE domain affect the pro-inflammatory properties of the protein (22). On the other hand, the PGRS domain exhibits the major sequence variations in clinical M. tuberculosis strains (20).…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the PGRS domain exhibits the major sequence variations in clinical M. tuberculosis strains (20). The PGRS fragment mediates the interaction with toll-like receptor 2 (TLR2) triggering host-cell death (14, 22). Deletions inside this domain can modulate the secretion of TNF-α induced by the PE_PGRS33 (14).…”

Section: Introductionmentioning

confidence: 99%

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The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans

et al. 2014

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The PE_PGRS33 protein is a member of the PE family, which encompasses the PE and the PE_PGRS subfamilies. Among PE_PGRS’s, this protein is one of the most studied antigens and its immunomodulatory properties are influence by both PE and PGRS domains. However, the contribution of these domains to the host immune recognition of the PE_PGRS33 protein and their potential role in latent tuberculosis infection in humans is still unknown. In this study, the immunogenic properties of the complete PE_PGRS33 protein and each domain separately were evaluated in BALB/c mice and latent tuberculosis infected (LTBI) humans. In mice, PE_PGRS33 and its domains induced similar antibody production and secretion of IFN-γ. PE_PGRS33 and the PE domain stimulated higher CD4+ and CD8+ T-cell proliferation compared to the PGRS domain. This demonstrated that the principal difference in the immune recognition of the domains is the higher activation of T-cell subpopulations involved in the control of tuberculosis. In humans, the secretion of IFN-γ in response to PE_PGRS33 was detected in both LTBI and in non-infected vaccinated individuals. The same was observed for antibody response, which targets epitopes located in the PGRS domain but not in the PE domain. These observations suggest that T and B cell responses to PE_PGRS33 are induced by BCG vaccination and can be maintained for many years in non-infected individuals. This also indicates that the IFN-γ response detected might not be associated with latent tuberculosis infection. These results contribute to the elucidation of the role of the PE_PGRS33 protein and its PE and PGRS domains in the immune response against Mycobacterium tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans

et al. 2014

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“…Varied transcription level of several PE/PPE genes within macrophages or mouse during MTB infection [10] suggested roles in the interaction with host macrophage. Cell wall associated PE/PPE family proteins [11–16] might directly interact with host cell surface receptor, or even disrupts the host immunity [14, 17–20]. …”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosisPPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

et al. 2016

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Tuberculosis, caused by Mycobacterium tuberculosis (MTB) infection, remains a grave global public health burden which claims the lives around two to three million annually. PE and PPE proteins, featured by the Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs at the conserved N-terminal domain, are abundant in the MTB genome. PPE32 can increase intracellular survival of mycobacteria through abnormally increase in cytokines production. PPE32 might subvert the macrophage immune response and thwart its bactericidal effect. THP-1 macrophages treated with PPE32 or infected with Mycobacterium smegmatis (MS) expression PPE32 showed increase of cytokines production and multiple hallmarks of apoptosis. We found that PPE32 significantly increases the expression of IL-12p40 and IL-32 through ERK1/2 signaling pathway. In addition, the cell viability of macrophage was inhibited after PPE32 stimulation. We noted that PPE32 induces cleavage of caspase-3 and caspase-9, while inhibition of caspase activity significantly abrogates the PPE32-induced cell apoptosis. Moreover, PPE32 treatment promotes endoplasmic reticulum stress related gene expression, suggesting ER stress might be responsible for PPE32-induced cell apoptosis.

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“…A monoclonal antibody directed against arabinomannan was capable of protecting mice despite lacking bactericidal activity or any ability to inhibit infection or bacterial replication and protection was associated with reduced immunopathology in the lung [141]. The characterization of the M. tuberculosis proteome in vivo provided a detailed list of the proteins deployed by the tubercle bacilli in necrotic and caseous lesions [142], which showed an unanticipated accumulation, among the most abundant proteins, of PE_PGRS proteins, which may promote inflammatory responses and induce tissue damage [143]. The functional and immunological characterization of the most abundant proteins detected in the caseous lesions may lead to the identification of new antigens that could serve as targets of antibodies aimed at neutralizing the proinflammatory responses.…”

Section: • • Targeting the Different Steps In Tb Pathogenesismentioning

confidence: 99%

Mycobacterium Tuberculosis Virulence: Insights and Impact on Vaccine Development

et al. 2015

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The existing TB vaccine, the attenuated Mycobacterium bovis strain BCG, is effective in protecting infants from severe forms of the disease, while its efficacy in protecting adults from pulmonary TB is poor. In the last two decades, a renewed interest in TB resulted in the development of several candidate vaccines that are now entering clinical trials. However, most of these vaccines are based on a common rationale and aim to induce a strong T-cell response against Mycobacterium tuberculosis. Recent advancements in the understanding of M. tuberculosis virulence determinants and associated pathogenic strategies are opening a new and broader view of the complex interaction between this remarkable pathogen and the human host, providing insights at molecular level that could lead to a new rationale for the design of novel antitubercular vaccines. A vaccination strategy that simultaneously targets different steps in TB pathogenesis may result in improved protection and reduced TB transmission.

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Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 ofMycobacterium tuberculosis

Cited by 38 publications

References 31 publications

The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans

The PGRS Domain from PE_PGRS33 of Mycobacterium tuberculosis is Target of Humoral Immune Response in Mice and Humans

Mycobacterium tuberculosisPPE32 promotes cytokines production and host cell apoptosis through caspase cascade accompanying with enhanced ER stress response

Mycobacterium Tuberculosis Virulence: Insights and Impact on Vaccine Development

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