Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors

Abstract

SummaryToll-like receptors (TLRs) recognize Mycobacterium tuberculosis (Mtb) or Mtb components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signalling cascades involved in the TLR-initiated immune response to mycobacterial infection. Although both TLR2 and TLR4 have been implicated in host interactions with Mtb, the relationship between specific mycobacterial molecules and various signal transduction pathways is not well understood. This review will discuss recent studies indicating critical roles for mycobacteria and mycobacterial components in regulation of mitogenactivated protein kinases and related signal transduction pathways that govern the outcome of infection and antibacterial defence. To better understand the roles of infection-induced signalling cascades in molecular pathogenesis, future studies are needed to clarify mechanisms that integrate the multiple signalling pathways that are activated by engagement of TLRs by both individual mycobacterial molecules and whole mycobacteria. These efforts will allow for the development of novel diagnostic and therapeutic modalities for tuberculosis that targets the intracellular signalling pathways permitting the replication of this nefarious pathogen.

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

“…The Toll-like receptors (TLR) are key sensors of M. tuberculosis infection and play an important role in shaping up the innate immune responses of the host (11)(12)(13)(14). A number of mycobacterial proteins and lipids are found to be involved in mediating signals through the TLRs (11).…”

“…A number of mycobacterial proteins and lipids are found to be involved in mediating signals through the TLRs (11). TLRs are a group of pattern recognition receptors that are capable of recognizing several pathogen-specific ligands and produce diverse arrays of cytokines that regulate the effector functions of the macrophages (12)(13)(14).…”

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

“…Additionally, MAPK pathways are activated by Mtb or its components and play an essential role in the regulation of innate immune signaling during mycobacterial infection (6). Because intracellular survival of Mtb plays a central role in its pathogenesis (7), it is important to understand the survival strategies of this bacterium within macrophages.…”

“…In mycobacterial infection, host innate immune responses may play a crucial role in early protection against Mtb infection, leading to establishment of effective adaptive immunity to tuberculosis (6). Additionally, MAPK pathways are activated by Mtb or its components and play an essential role in the regulation of innate immune signaling during mycobacterial infection (6).…”

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…TLRs shown to be key players in triggering immunity against M.tb infection are TLR2 (alone or as a heterodimer with TLR1 or TLR6), TLR9, and probably TLR4 . TLR2 alone or dimerized with TLR1 or TLR6, is shown to trigger a strong pro-inflammatory response by recognizing M.tb 19 KDa lipoglycoprotein, lower-and higher-order PIMs, LM and TDM [reviewed in (Jo et al, 2007)]. This pro-inflammatory response via TLR2 is shown to be mediated through its adaptor protein myeloid differentiation primary-response protein 88 (MyD88) , triggering a nuclear factor kappa-light chain-enhancer of activated B cell (NFB) signaling cascade through the recruitment of MyD88 and TIRAP (toll-interleukin 1 receptor [TIR] domain containing adaptor protein) (Kawai & Akira, 2010).…”