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Microbial Signaling through Toll-like receptors

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The discovery of Toll, (in fruit fly) and their mammalian homologues Toll-like receptors (TLRs), discoveries for which Jules Hoffman and Bruce Beutler were awarded half of the 2011 Nobel Prize in Medicine and Physiology, marked a major turning point in our understanding of how the host innate immune system ...

The discovery of Toll, (in fruit fly) and their mammalian homologues Toll-like receptors (TLRs), discoveries for which Jules Hoffman and Bruce Beutler were awarded half of the 2011 Nobel Prize in Medicine and Physiology, marked a major turning point in our understanding of how the host innate immune system recognizes and responds to microorganisms. TLRs, transmembrane proteins consisting of 13 members (TLR1-10 in humans, TLR1-9 and TLR11-13 in mice) are innate immune receptors localized on the cell surface or endosomal compartments where microorganisms are first encountered. As such they represent the first line of sentinels that alerts the host of biological dangers. Each TLR detects a discrete set of microbial associated molecular patterns (MAMPs). The cell surface TLRs recognize mainly microbial membrane components such as glycolipids and lipopeptides (TLR1, 2, 6), lipopolysaccharide (TLR4) or proteins (e.g flagellin) while TLRs confined to endosomes (TLR3, 7/8, 9) predominantly recognise microbial nucleic acids released in such degradative compartments.

TLRs recognize their cognate ligands through leucine-rich repeat ectodomains and activate downstream signalling cascades via the Toll/IL-1R (TIR) intracellular domain. TLRs transmit intracellular signals via two main TIR containing adaptors MyD88 and TRIF. With the exception of TLR3 which exclusively signals via TRIF, the MyD88 dependent pathway is triggered via all TLRs. TLR4 holds a unique position in that it signals both via the MyD88 and TRIF pathways. TLR triggering leads to the activation of several key downstream pathways including NF-B, Mitogen Activated Protein Kinases (MAPKs) and Interferon Regulatory Factors (IRF) pathways. Together these pathways control the expression and release of molecules such as NO and reactive oxygen species that mediate pathogen killing as well as pro-inflammatory cyto/chemokines and interferons that coordinate the innate and the subsequent immune responses. Accordingly, genetic mutations resulting in impaired activation of TLRs or the downstream signalling pathways are associated with enhanced susceptibility to microbial infections or inflammatory disorders.

In view of the diversity of MAMPs, in principle any pathogen can be recognized by multiple TLRs. However to mitigate anti-microbial host defences, successful pathogens have evolved strategies that enable them to evade, suppress or delay activation of immune signalling pathways including those via TLRs. Thus the outcome of host-microbial interaction is the product of the balance between innate immune receptor activation and immune escape mechanisms often mediated by microbial virulence factors. The nature of these complex interactions, which varies from one infection to another are not well understood. Furthermore, although primarily evolved to elicit protective host defences it is apparent that excessive activation of TLRs can be very harmful to the host. Hence to mitigate the negative effects of uncontrolled immune responses, in equal measures, the host has evolved intricate regulatory mechanisms as aimed at optimizing anti-microbial host defences with minimal collateral damage to the host. Breakdown in such regulatory mechanisms often results in life threatening immunopathologies (e.g sepsis, inflammatory bowel diseases and psoriasis just to mention a few examples) not only as a result of infections but also in response to the non-infectious commensal. In this Research Topic we aim to feature contributions of different types (Original Research, Methods, Hypothesis & Theory, e.t.c) focusing on role and mechanisms of TLR activation/regulation during host-microbial interactions.


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