Innate Immune Evasion

Innate immune defence has evolved to protect us from foreign invaders. It can quickly (seconds to minutes!!!) kill, destroy, and detoxify microbes and microbial structures. It is designed by evolution to recognize all bacteria, viruses, parasites and fungi, not only the pathogens. Recognition is through evolutionary conserved structures by a few dozen of innate recognition molecules. These recently identified important recognition molecules are present on the membrane of immune cells or as soluble molecules in serum. Only the microbes that escape this innate immunity are prone to become pathogenic. But bacteria are smart too. In the past years we have identified a great variety of novel immune evasion molecules from different bacteria that specifically target these innate recognition molecules. These molecules form now a novel family of bacterial virulence factors that discriminates itself from excreted toxins and capsule formation. They contribute to a great extent to the infection process. Typical for this new group of virulence factors is: they are all excreted, small (10-20 kDa) proteins, their efficacy is very high, the affinity for specific innate immune receptor molecules is extremely high (nM range), the specificity restricts itself to sometimes one but mostly two target molecules and they are non-toxic. We hypothesize that this family of evading molecules is much larger and also includes unknown inhibitors of the most important families of innate recognition molecules; the Toll like receptors and the components of the lectin pathway of complement. We propose here to have two PhD students identify these inhibitors and unravel their mechanism of action. This in order to gain substantial and important knowledge on: 1. The pathophysiology of infections caused by this bacterium. 2. The role of the receptor and antagonist in bacterial pathogenesis. 3. The structure and functioning of the antagonist. 4. The relative role of the receptor in innate immunity. 5. The structure and functioning of the receptor. 6. The potential use in anti-inflammatory therapeutics. The value of a specific inhibitor should not be underestimated in experimental research. Biochemical pathways are complex, parallel, synergistic and redundant. To identify the relative importance of each pathway or molecule in vitro or in vivo, the use of specific inhibitors has proven value through the history of science. The proposed work will be embedded in a strong and focussed group of staff, post-docs and technicians that are all working in the field of innate immune evasion. Furthermore the combination of the hunt for, the finding of, and the description of the mechanism of action is the perfect basis for a thesis. It is challenging and highly motivating for a PhD student to work on - your own - molecule.