Role of mycobacteria effectors in phagosome maturation blockage and new drug targets discovery

Abstract

Tuberculosis remains a serious global health threat with nearly 10 million new cases and 1.7 million deaths every year. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) further complicates this problem. It is pressing to find new ways to combat Mtb. The success of Mtb is largely attributed to its ability to persist within macrophages by arresting phagosomal maturation. The bacterial proteins and lipids play important roles in this inhibition which involves several aspects of phagosomal maturation, including both fusion and fission events and recruitment of V-ATPases allowing acidification. Understanding the interaction between the pathogen and host macrophage is essential to eradicate or control tuberculosis. This review focuses on the mechanism of phagolysosome formation, the pivotal event for the fates of infection participants and abundance of novel drug targets.

Mycobacterium tuberculosis Rv3402c Enhances Mycobacterial Survival within Macrophages and Modulates the Host Pro-Inflammatory Cytokines Production via NF-Kappa B/ERK/p38 Signaling

“…Subsequently, the phagosome matures through fusion with late endosomes and lysosomes, creating an inhospitable environment for invading microorganisms, that includes phagosomal acidification, elevated levels of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), charged antimicrobial peptides [1] and iron deprivation [2]. However, Mtb has evolved a spectrum of subversive strategies to survive and thrive inside the macrophages [3].…”

Infection of A549 human type II epithelial cells with Mycobacterium tuberculosis induces changes in mitochondrial morphology, distribution and mass that are dependent on the early secreted antigen, ESAT-6

“…Mtb classically enters the host in aerosolized droplets that are delivered to the alveolar passages. After gaining entry into host cells it employs mechanisms to avoid destruction by inactivating host cell defenses in order to replicate in a safe environment [2]. Once bacterial numbers inside the host cell have reached a threshold, host cell necrosis is induced [3] and the bacilli are able to escape, disseminate and repeat the cycle in neighboring cells.…”

Secreted Acid Phosphatase (SapM) of Mycobacterium tuberculosis Is Indispensable for Arresting Phagosomal Maturation and Growth of the Pathogen in Guinea Pig Tissues

“…There are an estimated 440,000 new cases of MDR-TB, 25,000 cases of XDR-TB and 1.1 million cases of TB-HIV co-infection globally every year [1], [2]. Despite the multitude of immune defense mechanisms that the host deploys against M.tuberculosis , the pathogen can continue to persist owing to its subtle tactics [3]. M.tuberculosis is inhaled via the droplet nuclei and then taken up by alveolar macrophages [3].…”

“…Despite the multitude of immune defense mechanisms that the host deploys against M.tuberculosis , the pathogen can continue to persist owing to its subtle tactics [3]. M.tuberculosis is inhaled via the droplet nuclei and then taken up by alveolar macrophages [3]. The outcome of the infection largely depends on the interaction between the host and the pathogen, especially within the macrophages [4].…”