Defining the 'Glycointeractome' of Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a major multi-drug resistant nosocomial pathogen and the cause of a significant number of hospital-acquired infections worldwide for which new treatment options are urgently needed. Due to the multi-drug resistance and prevalence of A. baumannii it is considered a critical top priority pathogen for research and development of new therapies and treatments by the World Health Organisation (WHO) and Centres for Disease Control and Prevention (CDC). A. baumannii encodes several major outer membrane proteins, called adhesins, that have all previously been determined to be involved in host adherence, and more broadly in pathobiology. However, the specific host receptors that these outer-membrane proteins interact with remains undefined. Our lab has demonstrated, for the first time, that a major A. baumannii surface adhesin, Ata, interacts with host glycans with high affinity. Ata bound to terminal and core galactose and Nacetylglucosamine structures with high affinity. The interaction of Ata with the host extracellular matrix (ECM) protein fibronectin, which is heavily glycosylated, was absolutely dependent of the presence of these glycan structures, as no interaction between Ata and deglycosylated fibronectin occurred. This Masters research project, demonstrates that the major outer-membrane protein from A. baumannii, OmpA, interacts with host glycans. Using a parallel approach of heterologousover-expression of OmpA at the E.coli cell surface, characterisation of purified protein, and study of knock-out mutants in A. baumannii, demonstrated that this major A. baumannii virulence factor interacts directly with host glycan moieties such as; Lewis antigens, Blood group H antigen, fucosyllatose structures, O-glycans like Tn and sTn. This knowledge will enable further investigation of precisely how A. baumannii interacts with the human host and pave the way for new ways to treat infections caused by a major human pathogen for which traditional antibiotics are rapidly becoming ineffective.