Role of glycans in bacteria-host interactions

点击翻译按钮获取中文摘要

Title: Role of glycans in bacteria-host interactions Bacteria adhere to mammalian cells through both highly specific and non-specific interactions. Mucous membranes lined with mucin glycoproteins are a first line of defense against invading microbes. In addition, bacteria can form biofilms that present a defense against the immune system. Of critical world wide importance are bacteria that have developed antibiotic resistance such as Acinetobacter baumannii. The extracellular polysaccharides of bacteria play important roles in the highly complex and dynamic interactions with the host, protecting bacteria from the host immune system, harsh environment and antibiotics, and are important virulence factors and are critical for the formation of biofilms. The molecular details and mechanisms of A. baumannii adhesion to the host and within biofilms are mostly unknown. The biosynthetic enzymes and mechanisms leading to complex glycans in bacteria also remain elusive. Our past research has focused on the biosynthesis of mammalian glycoproteins that are receptors for bacteria and are regulated during inflammation and in many diseases. Subsequently we discovered biosynthetic pathways in the synthesis of O antigens with a focus on pathogenic bacteria. We will now combine these two areas of expertise in defining the mechanisms and structural details of the interactions between bacteria and host mucus. We will thus address bacteria-host interactions by a) defining the enzymes and mechanisms of bacterial polysaccharide synthesis, b) studying the role and inhibition of specific bacterial enzymes in biofilm formation and mucus adhesion. c) determining the roles of mucus structures in bacterial interactions, d) developing methods to reduce bacteria-host interactions. The results from these studies will fill a gap in our knowledge of A. baumannii virulence factors and will lead to development of methodologies to reduce adhesion to host mucosa, to block biofilm formation and reduce bacterial infection. The project includes the reengineering of mucin glycans in order to explore their role in bacterial adhesion. With a team of collaborators and expertise in glycobiology we will provide substrates and explore bacterial protein glycosylation pathways and mechanisms. The design of inhibitors and deletion of genes encoding specific enzymes in the pathway will reveal their role in polysaccharide assembly, in biofilm formation and host interactions. In the proposed work, students will have the opportunity to discover new mechanisms of polysaccharide assembly, to study bacterial biofilm formation and adherence to human cells, analyze glycan structures critical for bacterial interactions, bioinformatics, transfection methods, glycan and protein structures and develop drug targets. The knowledge gained in this work can be translated into new anti¬bacterial strategies that are urgently needed in light of life threatening antibiotic resistance.