Grant: Discovery Grants Program - Individual

Bacterial pathogens dramatically alter host cell function to overcome innate and acquired immune responses and to establish a niche inside host cells. During these complex host-pathogen interactions, pathogens force their hosts to accommodate them in so-called bacterium-containing compartments (BCCs). To form BCCs, bacteria secrete proteins that alter normal cellular functions including signaling pathways or vesicle trafficking control. These subverted host functions then abandon their regular role and support the development of the BCC and promote bacterial growth by providing nutrition and protection. The formation and maturation of these compartments is complex and only parts of the underlying interactions between bacteria and host are understood. Recently, we developed a novel mass spectrometry-based method to tease out the composition of BCCs in Salmonella enterica serovar Typhimurium, a common food-borne pathogen. A key finding of our study was that Salmonella is manipulating more host functions than previously anticipated, including organelles that were believed to be utilized only by other bacterial species. This program intends to build on these insights and will develop and implement methods to reveal the molecular mechanisms underlying the crosstalk between host and microbe. Over the long term we will gain a more complete view of the involved molecular targets, explore hitherto unknown interactions and identify key host mechanisms that may be preferentially targeted by bacteria. These findings are expected to provide mechanistic insights into the co-evolutionary arms race between host and microbes. In the short term, our goals are to investigate the nature of the newly identified interactions between Salmonella and HeLa cells. Knockdown experiments of the novel host components will reveal their importance for the formation and composition of Salmonella BCCs. Proteome analysis of Salmonella isolated from these altered BCCs will indicate whether the bacterium faces different nutritional challenges as a consequence of BCC composition changes. We will further perform interaction studies to identify the bacterial proteins involved in hijacking the novel host components. Together, the work will expand our fundamental understanding of Salmonella-host interactions and provide insights how Salmonella can reside in a variety of host organism and cell types. By understanding those strategies with which Salmonella can adapt to different intracellular conditions it may be possible to develop intervention strategies to prevent infection of livestock and humans and thereby improve food safety.