Crosstalk between Mycobacterium tuberculosis and the host cell

Abstract

The successful establishment and maintenance of a bacterial infection depend on the pathogen's ability to subvert the host cell's defense response and successfully survive, proliferate, or persist within the infected cell. To circumvent host defense systems, bacterial pathogens produce a variety of virulence factors that potentiate bacterial adherence and invasion and usurp host cell signaling cascades that regulate intracellular microbial survival and trafficking. Mycobacterium tuberculosis, probably one of the most successful pathogens on earth, has coexisted with humanity for centuries, and this intimate and persistent connection between these two organisms suggests that the pathogen has evolved extensive mechanisms to evade the human immune system at multiple levels. While some of these mechanisms are mediated by factors released by M. tuberculosis, others rely on host components that are hijacked to prevent the generation of an effective immune response thus benefiting the survival of M. tuberculosis within the host cell. Here, we describe several of these mechanisms, with an emphasis on the cyclic nucleotide signaling and subversion of host responses that occur at the intracellular level when tubercle bacilli encounter macrophages, a cell that becomes a safe-house for M. tuberculosis although it is specialized to kill most microbes.

Keywords: Cyclic AMP; Cyclic di-AMP; Immunity; Interferon; Macrophage; Mycobacterium tuberculosis.

Figure 1. cAMP-mediated signaling in M. tuberculosis infection

Macrophages produce intracellular cAMP through G-protein-coupled receptor (GPCR)-adenylate cyclases (ACs). Increased cAMP stimulates protein kinase A (PKA) leading to the phosphorylation of cAMP response-element-binding protein (CREB), and subsequent transcriptional changes including modulation of cytokine expression. M. tuberculosis secretes cAMP directly into host macrophages leading to increased intracellular cAMP levels following infection. The M. tuberculosis infection-induced cAMP burst activates the PKA–CREB pathway leading to production of TNF-α, one of the key cytokines for TB granuloma formation. P = phosphate, TNF-a = tumor necrosis factor-a, CBP = CREB-binding protein, ERK1/2 = extracellular-signal-regulated kinase-1/2, p38 = p38 mitogen-activated protein (MAP) kinase.

Figure 2. Cyclic dinucleotide signaling in M. tuberculosis infection

Cyclic dinucleotides (c-di-AMP and c-di-GMP) secreted by either phagosomal or cytoplasmic M. tuberculosis are detected by host cytoplasmic receptors DDX41 and STING. Receptor-bound DDX41 also interacts with and activates STING. Activated STING subsequently interacts with and activates kinase TBK1 leading to phosphorylation and dimerization of IRF3 which translocates into the nucleus and stimulates transcription of Type-1 IFN response genes. Activated STING also co-localizes with LC3, an autophagosome membrane component, and initiates autophagosome formation that ultimately leads to bacterial degradation. Correspondingly, bacterial DNA gains access to the cytosolic compartment and binds to the dsDNA receptor cyclic-GAMP synthase (cGAS) stimulating the synthesis of 2′,3′-cGAMP. Host-produced cGAMP binds to STING and stimulates a signaling cascade similar to that of the bacterial cyclic dinucleotides. P = phosphate, IFN = interferon, STING = stimulator of interferon genes, TBK1 = TANK-binding kinase 1, IRF3 = interferon regulatory factor 3.