Rapid Evolution of Bacterial Exotoxin B Subunits Independent of A subunits: Sialic Acid Binding Preferences Correlate with Host Range and Intrinsic Toxicity

Abstract

Several well‐known AB bacterial toxins have cytotoxic A subunits that are delivered to the cytosol following B subunit binding to terminal sialic acid‐presenting glycans on host cell surfaces. Phylogenetic analysis of known and predicted B subunits in available genomes showed a poor correlation with that of associated A subunits, or even with that of the bacterial species phylogeny. In some cases, such as an exported protein of Yersinia pestis (YpB) there also appears to be no associated A subunit encoded in the genome. Y. pestis is the etiologic agent of Plague, responsible for major devastating epidemics in human history and is of global importance to public health and biodefense. Plague can never be eradicated because of the adaptability of the organism to infect more than 200 known host species. We noted that YpB shares 58% identity/79% similarity with the homopentameric B subunit of Subtilase cytotoxin, an AB5 toxin of E. coli, which also has 48% identity/68% similarity with that of the A2B5 S. Typhi typhoid toxin. We previously studied binding of such toxin B5 pentamers to a sialoglycan microarray and shown selective binding to different kinds of sialic acids that happen to be enriched in corresponding host cells, such as N‐acetylneuraminic acid (Neu5Ac; prominent in humans) or N‐glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Consistent with the much broader host range of Y. pestis, we have now found that YpB binds to essentially all types of sialic acids studied including Neu5Ac, Neu5Gc and their modified versions, and even to Kdn (2‐keto‐3‐deoxy‐D‐glycero‐D‐galacto‐nononic acid) a sialic acid prominent in reptiles and amphibians. Notably, YpB toxin alone can cause cytotoxicity that is abolished by mutations eliminating sialic acid recognition, suggesting that both uncontrolled cell proliferation and cell death might be mediated via lectin‐like cross‐linking of cell surface glycoproteins. These findings may help explain the wide host range of Y. pestis and could be important for understanding pathogenic mechanisms. Taken together, the data suggest Red Queen effects that are driving ongoing rapid evolution of both host sialic acids and pathogen toxin binding properties. Further studies of this clade of B5 toxins are revealing additional correlations of sialic acid binding preferences with host range and intrinsic toxicity, and molecular modeling studies are underway to define amino acid residues that determine binding differences.Support or Funding InformationNIH U01 CA199792This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.