Chemical proteomics inside us: Using chemical tools to decipher coexistence between bacteria and humans

点击翻译按钮获取中文摘要

Recent studies have shown that the traditional view of the human body as a static collection of roughly 100 trillion cells is misguided. Not only is the makeup of this collection highly diverse and strongly dissimilar between different individuals, but also the populations of different bacterial and fungal species (which together account for the majority of cells in our bodies) are in constant flux during the life cycle of an individual human being. We propose that both colonization and virulence are meticulously regulated by chemical crosstalk between bacterial species as well as by crosstalk between bacterial and host cells. Understanding thechemistry underlying these molecular encounters will help us to answer the following seminal questions: What happens when a population of pathogens starts to grow among healthy flora beyond their 'natural' limit?Specifically, how do the commensal species react to a sudden rise in specific signaling molecules, and how do they sense them? What prevents members of the healthy flora from being eradicated, and how can we use this information to prevent or treat dysbiosis? We aim to unravel the molecular details behind these types of chemical crosstalk by using an advanced chemical proteomics platform, based on the development of photoactivatable tag-free molecular probes (aim 1), in two distinct yet related settings: the human airways (aim 2) and the human gut (aim 3). Our overall objective is to identify and examine in detail thesmall molecules and proteins from known pathogens which serve as primary regulators of their relationship with each other and with the human host, and the small molecules and proteins from known and unknown gut bacteria that regulate the balance between intestinal health and dysbiosis. Our long-term objective is to answer the following fundamental questions: How do commensals and pathogens assess the exact chemical state of their environment? How do specific pathogens succeed in dominating certain niches and what is the role of our microbiome in preventing this? This team brings together precisely the disciplines required to effectively approach these seminal questions. The Meijler group has ample chemical and microbiological experience in the synthesis and application of probes based on bacterial signaling molecules and recently his group used this chemical proteomics platform successfully to elucidate part of the network of 4-alkyl-quinolone receptors in P. aeruginosa. The Elinav group has used their strong expertise in next-generation sequencing, immunology, and advanced germ-free mousemodels to reveal how microbiota alter host physiology and behaviour. The Mann group has revolutionized proteomics through the development of tools such as peptide sequence tags, the nano-electrospray ion source, MaxQuant, and stable isotope labeling of amino acids in cell culture (SILAC), that enable unprecedented analyses of proteomes in terms of width, depth and precision.