Dataset Information

Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.

ABSTRACT: Mycobacterium tuberculosis (M.tb) contrives intracellular abode as a strategy to combat antibody onslaught. Additionally, to thrive against hostile ambiance inside host macrophages, the pathogen inhibits phago-lysosomal fusion. Finally, to further defy host cell offensives, M.tb opts for dormant phase, where it turns off or slows down most of its metabolic process as an added stratagem. While M.tb restrains most of its metabolic activities during dormancy, surprisingly latency-associated alpha-crystallin protein (Acr-1) is expressed most prominently during this phase. Interestingly, several previous studies described the potential of Acr-1 to induce the robust immuno-prophylactic response in the immunized host. It is intriguing to comprehend the apparent discrepancy that the microbe M.tb overexpresses a protein that has the potential to prime host immune system against the pathogen itself. Keeping this apparent ambiguity into consideration, it is imperative to unravel intricacies involved in the exploitation of Acr-1 by M.tb during its interaction with host immune cells. The present study suggests that Acr-1 exhibits diverse role in the maturation of macrophages (M?s) and related immunological responses. The early encounter of bone marrow derived immune cells (pre-exposure during differentiation to M?s) with Acr-1 (AcrM?pre), results in hampering of their function. The pre-exposure of naïve M?s with Acr-1 induces the expression of TIM-3 and IL-10. In contrast, exposure of fully differentiated M?s to Acr-1 results in their down-modulation and induces the phosphorylation of STAT-1 and STAT-4 in host M?s. Furthermore, Acr-1 mediated activation of M?s results in the induction of Th1 and Th17 phenotype by activated T lymphocyte.

SUBMITTER: Mubin N

PROVIDER: S-EPMC6218195 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.

Mubin Nida N Pahari Susanta S Owais Mohammad M Zubair Swaleha S

PloS one 20181105 11

Mycobacterium tuberculosis (M.tb) contrives intracellular abode as a strategy to combat antibody onslaught. Additionally, to thrive against hostile ambiance inside host macrophages, the pathogen inhibits phago-lysosomal fusion. Finally, to further defy host cell offensives, M.tb opts for dormant phase, where it turns off or slows down most of its metabolic process as an added stratagem. While M.tb restrains most of its metabolic activities during dormancy, surprisingly latency-associated alpha-c ...[more]

PMID: 30395609

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Project description:Intracellular pathogenic bacteria, including Mycobacterium tuberculosis, frequently have multitiered defense mechanisms ensuring their survival in host phagocytic cells. One such defense determinant in M. tuberculosis is the katG gene, which encodes an enzyme with catalase, peroxidase, and peroxynitritase activities. KatG is considered to be important for protection against reactive oxygen and nitrogen intermediates produced by phagocytic cells. However, KatG also activates the front-line antituberculosis drug isoniazid, hence rendering M. tuberculosis exquisitely sensitive to this compound. In this context, katG expression represents a double-edged sword, as it is an important virulence determinant but at the same time its activity levels determine sensitivity to INH. Thus, it is important to delineate the regulation and expression of katG, as this not only can aid understanding of how M. tuberculosis survives and persists in the host but also may provide information of relevance for better management of INH therapy. Here, we report the first extensive analysis of the katG promoter activity examined both in vitro and in vivo. Using S1 nuclease protection analysis, we mapped the katG mRNA 5' ends and demonstrated that two promoters, P(1)furA and P(1)katG, control transcription of katG. The furA and katG genes are cotranscribed from P(1)furA. Both P(1)furA and P(1)katG promoters show induction upon challenge with hydrogen peroxide and cumene hydroperoxide. Studies carried out using the transcriptional fusions P(1)furA-gfp, P(1)katG-gfp, and P(1)furA-P(1)katG-gfp confirmed the existence of two katG promoters. In addition, we showed that both promoters are expressed in vivo during intracellular growth of virulent M. tuberculosis H37Rv. P(1)furA is induced early upon infection, and P(1)katG becomes active only upon extended growth in macrophages. These studies delineate the transcriptional organization of the furA-katG region and indicate differential regulation in vivo of the two katG promoters. These phenomena most likely reflect the differing demands at sequential stages of the infection cycle and may provide information for improved understanding of host-pathogen interactions in tuberculosis and for further optimization of INH chemotherapy.

Dataset Information

Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.

Publications

Mycobacterium tuberculosis host cell interaction: Role of latency associated protein Acr-1 in differential modulation of macrophages.

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