Abstract

Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.

Highlights

  • Innate immunity provides the first line of defense against invading pathogens

  • Stimulation of all Toll-like receptors (TLRs) activates the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) signaling pathways, both of which are critical for an effective immune response

  • This review describes the mechanisms bacteria use to inhibit TLR-dependent signaling, focusing on strategies that block MAPK and NF-κB signaling and

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Summary

INTRODUCTION

Recognition of microbial ligands, or pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs), stimulates innate immune cells to upregulate the expression of cytokines, chemokines, and proteins that directly target microbes. Stimulation of all TLRs activates the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) signaling pathways, both of which are critical for an effective immune response. Following detection of PAMPs by a TLR, signaling is initiated by the recruitment of adaptor proteins to the cytoplasmic Toll and IL-1 Receptor (TIR) domain of the receptor. MyD88 recruits IL-1 receptorassociated kinase (IRAK) 4, IRAK1 and IRAK2 to form a complex known as the Myddosome, which subsequently recruits the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6)

Subverting TLR Signaling by Bacteria
Salmonella Typhimurium Gastrointestinal disease
Shigella flexneri
BLOCKING SIGNALING BY MIMICKING TIR:TIR INTERACTIONS
BACTERIAL PROTEASES
BACTERIAL ACETYLTRANSFERASES
BACTERIAL PHOSPHOTHREONINE LYASES
BACTERIAL KINASES
OTHER BACTERIAL EFFECTORS
SUMMARY AND FUTURE PERSPECTIVES
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