The Innate Immune Response to Bacterial Infection: The Role of Toll-like Receptors (TLR)

Innate Immunity provides the first line of defense angainst infectious diseases. A primary challenge to the innate immune system is the recognition and discrimination of Potential pathogens from self. To meet this challenge, phagocytes recognize conserved motifs on microbes via a restricted number of pattern recognition receptors. Recently, Toll-like receptors (TLR) have emerged as key receptors responsible not only for the detection of a variety of microbial cell wall components but also for the initiation of an inflammatory immune response. The number of TLRs and their resepective ligands have increased within the last year and, in addition, evidence of interactions between different TLRs, eventually leading to an appropriate immune response, is growing. Knowledge of the biological role of TLR to host defense is mainly derived from in vitro experiments or in vivo studies with purified cell wall components. Having demonstrated that TLR4 deficient mice are more susceptible to pulmonary Gram-negative and, to some extent, Gram-positive infections, we intend to investigate the in vivo contribution of TLR2 in well established animal models of pneumonia and peritonitis with the help of TLR2 deficient mice. We then want to expand these studies and analyze the potential role of TLR`s interplay, i.e. the same in vivo infection models shall be used in TLR2/TLR4 (and later on TLR2/TLR6) double knock-out mice. This approach should allow us to discriminate and identify possible interactions between these TLRs in host defense in vivo and may contribute to a better understanding of distinctive, pathogen-specific immunostimulatory motifs.