Toll-like receptor biology : From evolution to function

Our environment contains many pathogens that pose a threat to our health. Fortunately, the immune system of humans and animals provides protection by timely detecting and neutralizing pathogens. Proteins called Toll-like receptors (TLRs) are part of the immune system and are important for detecting pathogens. How these receptors work exactly is not entirely understood and this limits the understanding of the role that these receptors play in diverse diseases. The importance of TLRs is also clear from the fact that these receptors have evolved more than 500 million years ago in prehistoric animals and are still present in almost all animals and humans today. During this long evolution differences occurred among the receptors of different animals. We used this natural variation to improve the understanding of TLRs. In our research we have synthetized the receptors of humans, fish, birds, lizards and even crocodiles and compared their function. This has lead to discoveries concerning the production of new receptors, the correct localization of receptors in a cell, the mechanism of receptor activation, and the species-specific detection of pathogens. The results in this thesis show that a species-comparative strategy is highly efficient for better understanding the evolution and functions of a protein. The new insights about TLRs may be used to strengthen our immune system and improve the development of medical drugs