MOLECULAR PATHOGENESIS

AB5 TOXINS

AB5 toxins are an important family of toxins that cause massive global morbidity and mortality, in humans and livestock. AB5 toxins exert their effects in a two-step process: (i) binding of the pentameric B subunit to specific glycan receptors on the target cell surface; (ii) internalisation of the AB5 toxin, followed by A subunit-mediated inhibition or corruption of essential host functions. The above AB5 toxins ultimately act on cytosolic targets, and so must be internalised, transported to the appropriate site and translocated across the respective organelle membrane. The AB5 toxins from each sub-family possess unique properties that arise from differing catalytic activities of the A subunit and/or differing receptor specificities of the B subunit.

HOST-PATHOGEN GLYCAN INTERACTIONS

Glycoconjugates cover the cell surface of all kingdoms of life, including viruses. Glycoconjugates are important as they can influence range of cellular functions such as cell growth, cell-cell interactions, immune defense, inflammation, viral and microbial infection. As such glycans play important roles in the pathogenesis of in range of pathogenic infections. The role of glycans in bacterial-host interactions is to produce proteins such as lectins, adhesins or toxins that attach to host's glycans that enable the bacteria to invade host tissues to cause disease. While in parasitic worms the role of glycans is more complex, they also produce lectins that enable disease progression but also their cell surface glycans perform important roles in immune evasion.

Conversely, Mammalian innate immunity carries a substantial burden of the defense function against pathogens and, therefore, it has evolved a range of receptors to detect these pathogens and defeat them. These receptors are termed pattern recognition receptors (PRR) which bind microbial surface molecules such as LPS and peptidoglycan in the process of non-self recognition. In particular, a range of lectins, a large family of proteins that bind glycans such as dectin-1 and mannose-binding protein are PRRs. However, mammalian hosts also express several lectins such as selectins and siglec that recognize self-glycans to tether leukocytes to endothelium and regulate signaling in leukocytes. Recently it has become increasingly clear that there are several lectins that cannot be exclusively segregated into lectins that recognize self or non-self glycans. This paradox highlights how little we know about host lectin repertoire. Our knowledge of the structural and biophysical aspects of host and pathogen glycan moieties and their interactions is fragmentary and warrants further investigation to understand their role in innate immunity.