Dataset Information

Role of PPE18 protein in intracellular survival and pathogenicity of Mycobacterium tuberculosis in mice.

ABSTRACT:

Background

Ever since its discovery the mycobacterial proline-proline-glutamic acid (PPE) family of proteins has generated a huge amount of interest. Understanding the role of these proteins in the pathogenesis of Mycobacterium tuberculosis (Mtb) is important. We have demonstrated earlier that the PPE18 protein of Mtb induces IL-10 production in macrophages with subsequent downregulation of pro-inflammatory cytokines like IL-12 and TNF-? and favors a T-helper (Th) 2-type of immune response.

Methodology/principal findings

Using a ppe18 genetic knock-out Mtb strain, we have now carried out infection studies in mice to understand the role of PPE18 in Mtb virulence. The studies reveal that lack of PPE18 leads to attenuation of Mtb in vivo. Mice infected with the ppe18 deleted strain have reduced infection burden in lung, liver and spleen and have better survival rates compared to mice infected with the wild-type Mtb strain.

Conclusions/significance

Taken together our data suggest that PPE18 could be a crucial virulence factor for intracellular survival of Mtb.

SUBMITTER: Bhat KH

PROVIDER: S-EPMC3532481 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Role of PPE18 protein in intracellular survival and pathogenicity of Mycobacterium tuberculosis in mice.

Bhat Khalid Hussain KH Ahmed Asma A Kumar Santosh S Sharma Pawan P Mukhopadhyay Sangita S

PloS one 20121228 12

<h4>Background</h4>Ever since its discovery the mycobacterial proline-proline-glutamic acid (PPE) family of proteins has generated a huge amount of interest. Understanding the role of these proteins in the pathogenesis of Mycobacterium tuberculosis (Mtb) is important. We have demonstrated earlier that the PPE18 protein of Mtb induces IL-10 production in macrophages with subsequent downregulation of pro-inflammatory cytokines like IL-12 and TNF-α and favors a T-helper (Th) 2-type of immune respon ...[more]

PMID: 23300718

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Project description:The stable infection of host macrophages by Mycobacterium tuberculosis (Mtb) involves, and depends on, the attenuation of the diverse microbicidal responses mounted by the host cell. This is primarily achieved through targeted perturbations of the host cellular signaling machinery. Therefore, in view of the dependency of the pathogen on host molecules for its intracellular survival, we wanted to test whether targeting such factors could provide an alternate route for the therapeutic management of tuberculosis. To first identify components of the host signaling machinery that regulate intracellular survival of Mtb, we performed an siRNA screen against all known kinases and phosphatases in murine macrophages infected with the virulent strain, H37Rv. Several validated targets could be identified by this method where silencing led either to a significant decrease, or enhancement in the intracellular mycobacterial load. To further resolve the functional relevance of these targets, we also screened against these identified targets in cells infected with different strains of multiple drug-resistant mycobacteria which differed in terms of their intracellular growth properties. The results obtained subsequently allowed us to filter the core set of host regulatory molecules that functioned independently of the phenotypic variations exhibited by the pathogen. Then, using a combination of both in vitro and in vivo experimentation, we could demonstrate that at least some of these host factors provide attractive targets for anti-TB drug development. These results provide a "proof-of-concept" demonstration that targeting host factors subverted by intracellular Mtb provides an attractive and feasible strategy for the development of anti-tuberculosis drugs. Importantly, our findings also emphasize the advantage of such an approach by establishing its equal applicability to infections with Mtb strains exhibiting a range of phenotypic diversifications, including multiple drug-resistance. Thus the host factors identified here may potentially be exploited for the development of anti-tuberculosis drugs.

Dataset Information

Role of PPE18 protein in intracellular survival and pathogenicity of Mycobacterium tuberculosis in mice.

Background

Methodology/principal findings

Conclusions/significance

Publications

Role of PPE18 protein in intracellular survival and pathogenicity of Mycobacterium tuberculosis in mice.

Similar Datasets

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