Combating Tuberculosis via Restoring the Host Immune Capacity by Targeting M. tb Kinases and Phosphatases

Abstract

Mycobacterium tuberculosis (M. tb) is a remarkably versatile pathogen that possesses a unique ability to counteract the host's defence mechanisms to control the infection. Several mycobacterial protein kinases and phosphatases were found to play a key role in impeding phagosome maturation in macrophages and accordingly blocking the phagosome-lysosome fusion, therefore allowing the bacteria to survive. During phagocytosis, both M. tb and the host's phagocytic cells develop mechanisms to fight each other, resulting in pathogen elimination or survival. In this respect, M. tb uses a phosphorylation-based signal transduction mechanism, whereby it senses extracellular signals from the host and initiates the appropriate adaptation responses. Indeed, the ability of M. tb to exist in different states in the host (persistent quiescent state or actively replicating mode) is mainly mediated through protein phosphorylation/dephosphorylation signalling. The M. tb regulatory and defensive responses coordinate different aspects of the bacilli's physiology, for instance, cell wall components, metabolic activity, virulence, and growth. Herein, we will discuss the implication of M. tb kinases and phosphatases in hijacking the host immune system, perpetuating the infection. In addition, the role of PknG, MPtpA, MPtpB, and SapM inhibitors in resetting the host immune system will be highlighted.

Keywords: MPtpA; MPtpB; PknG; SapM; host immune response; mycobacterial kinase inhibitor; mycobacterial kinases; mycobacterial phosphatase inhibitor; mycobacterial phosphatases.

Figure 1

Overview of the phagocytosis of microbial invaders and phagosome maturation, showing M. tb secreted kinases and phosphatases interfering with the developmental process of phagosomes. Generally, once engulfed, the pathogen remains confined within early phagosomes, which then undergo a maturation process that involves fusion with endosomes and lysosomes to eventually turn into phagolysosomes, the definitive pathogenicidal vacuoles, followed by fission and recycling of the endocytic vesicles. Early phagosomes are marked by the presence of EEA1, PI3P, and Rab5, which contribute to the phagosome–endosome fusion. Upon the procession of phagosomal maturation, V-ATPase accumulate on the phagosomal membrane, lowering the pH of phagosomal lumen. The acidic nature of phagolysosomes constitutes a harsh environment for the microbes and is a prerequisite for the activation of several hydrolytic enzymes. Subsequently, the antigen is degraded and presented, alerting the adaptive immune system. M. tb-secreted virulence factors PknG, MPtpA, MPtpB, and SapM impair the phagolysosome fusion, allowing the bacteria to survive. MPtpA impedes phagosome acidification via hydrolysing VPS33B and inhibiting the trafficking of V-ATPase to late phagosomes. MPtpB hydrolyses PI3P and PI(3,5)P₂ that mediate the transition to late phagosomes and phagolysosome, respectively. Similar to MPtpB, SapM blocks the preceding transition events via hydrolysing PI(4,5)P₂, PI3P and binding to Rab7.