Grant: Operating Grant

Our immune system can detect an integral component of bacterial surfaces called lipid A. This is mediated by a receptor complex called TLR4-MD-2, that when activated, results in the production of proteins called cytokines that are important in controlling infection. Although not completely understood, much of what is known about this process has arisen from studying lipid A from laboratory strains of E. coli and a handful of pathogens. These studies have shown that lipid A molecules vary not only between bacterial pathogens but also within a given strain. This can result in immune responses that differ both in the magnitude, and in the pattern of cytokines produced. This can ultimately shape the outcome of infection. Bordetella pertussis, the causative agent of whooping cough, which has a lipid A molecule that is very different from that of E. coli, can alter its lipid A to either increase or dampen the immune response to it. How this happens is not known. We will decipher the mechanisms by which very small changes in B. pertussis lipid A influence immune responses. We will also look at the mechanisms by which the lipid A molecule is modified in B. pertussis. This work will contribute to the basic knowledge on how a fundamental building block of an important bacterial surface structure is made, and how the host responds to it.