Pattern recognition receptors and cytokines in Mycobacterium tuberculosis infection--the double-edged sword?

Abstract

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a major cause of human death worldwide. Innate immunity provides host defense against Mtb. Phagocytosis, characterized by recognition of Mtb by macrophages and dendritic cells (DCs), is the first step of the innate immune defense mechanism. The recognition of Mtb is mediated by pattern recognition receptors (PRRs), expressed on innate immune cells, including toll-like receptors (TLRs), complement receptors, nucleotide oligomerization domain like receptors, dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (DC-SIGN), mannose receptors, CD14 receptors, scavenger receptors, and FCγ receptors. Interaction of mycobacterial ligands with PRRs leads macrophages and DCs to secrete selected cytokines, which in turn induce interferon-γ- (IFNγ-) dominated immunity. IFNγ and other cytokines like tumor necrosis factor-α (TNFα) regulate mycobacterial growth, granuloma formation, and initiation of the adaptive immune response to Mtb and finally provide protection to the host. However, Mtb can evade destruction by antimicrobial defense mechanisms of the innate immune system as some components of the system may promote survival of the bacteria in these cells and facilitate pathogenesis. Thus, although innate immunity components generally play a protective role against Mtb, they may also facilitate Mtb survival. The involvement of selected PRRs and cytokines on these seemingly contradictory roles is discussed.

Figure 1

Pathogenesis and transmission profile of Mtb. Adequate innate immunity is believed to protect the host from Mtb infection in the majority of people, while inadequate innate immune response leads to Mtb infection. The adaptive immunity then restricts Mtb growth which leads to Mtb containment in granulomas which causes latent TB infection. Defective adaptive immunity causes active TB and promotes reactivation of the latent TB.

Figure 2

Immune recognition of M. tuberculosis during phagocytosis. Several pattern recognition receptors (PRRs) on phagocytic cells have been identified for the recognition of conserved pathogen associated molecular patterns (PAMPs) of mycobacteria. TLR2 recognizes the 19 kDa lipoprotein (LP), lipomannan (LM), and lipoarabinomannan (LAM). TLR1-TLR2 and TLR6-TLR2 heterodimers bind diacylated and triacylated LP, respectively. TLR4 binds tri- and tetra-acylated LM, heat shock protein 65 (HSP65), and 50S ribosomal protein (50S RP), whereas mycobacterial DNA is recognized by phagosomal TLR9. Complement receptors (CRs) are mainly responsible for uptake of opsonized M. tuberculosis, while mannose receptors (MRs) and scavenger receptors (SR) are for uptake of nonopsonized M. tuberculosis. Cytosolic receptor NOD2 interacts with Mtb derived peptidoglycan component muramyl dipeptide (Mtb-MDP). MyD88 is the key component in TLR-mediated defense mechanism whose downstream signaling cascade leads to the activation of NF-κB transcription factor and to the production of inflammatory molecules. TLRs are expressed on phagocytic cell surface and in phagosomes. Dashed arrow represents the presence of numerous signaling molecules in between.