Polymorphisms in members of the Toll-like receptor signalling pathway and their role in infectious disease

Abstract

Toll-like receptors (TLRs) play an important role in mediating the host's response to invading pathogens. In humans, they comprise of a family of ten pattern recognition receptors (PRRs) located on innate immune cells. They mediate pro-inflammatory signals through their Toll/Interleukin-1/Receptor (TIR) domains by recruiting adaptor molecules through TIR/TIR interactions. Down-stream signals are mediated through a combination of phosphorylation, ubiquitination and degradation events; finally culminating in the transcription of pro-inflammatory genes which initiate the antimicrobial response. Work presented in this thesis demonstrates that non-synonymous polymorphisms (SNPs) present in TLR6 and the TLR adaptor MyD88 adaptor like (Mai) play a role in the pathogenesis of infectious disease. A serine to leucine SNP at position 180 of Mai provides protection from infectious diseases, malaria, tuberculosis (TB), invasive pneumococcal disease (IPD) and bacteraemia. Individuals who are heterozygous for Mai (SI80/Ll80) have half the risk of suffering from malaria, TB, bacteraemia and IPD with a fourfold decreased risk of severe malaria. A non-synonymous SNP found in TLR6 at position 30 changes aspartic acid to an asparagine, and causes a seven fold increase in susceptibility to IPD and septicaemia. The microbes which mediate these diseases are known to be recognised by extracellular TLRs such as TLR4, TLR2 and TLR6, providing a link between the presence of the invading pathogen and the TLR signalling system. Utilising this information two questions arose, firstly, "could this genetic information be used to understand more about the biochemistry of Mai and TLR6?" and secondly, "could a mechanistic explanation be provided for the genetic association of Mai and TLR6 with disease?"