Bacterial AB toxins and host-microbe interactions

Abstract

AB toxins are protein virulence factors secreted by many bacterial pathogens, contributing to the pathogenicity of the cognate bacteria. AB toxins consist of two functionally distinct components: the enzymatic "A" component for pathogenicity and the receptor-binding "B" component for toxin delivery. Consistently, unlike other virulence factors such as effectors, AB toxins do not require additional systems to deliver them to the target host cells. Target host cells are located in the infection site and/or located distantly from infected host cells. The first part of this review discusses the structural and functional features of single-peptide and multiprotein AB toxins in the context of host-microbe interactions, using several well-characterized examples. The second part of this review discusses toxin neutralization strategies, as well as applications of AB toxins relevant to developing intervention strategies against diseases.

Keywords: AB toxin; Adjuvant; Antibody; Bacteria; Host and microbe interaction; Pathogen; Pathogenicity; Structure and function; Toxin neutralization; Toxin synthesis, secretion, and delivery; Vaccine; Virulence.

Fig. 1

Schematic diagrams of single-peptide and multiprotein AB toxins. (A) AB toxins are protein virulence factors secreted by many bacterial pathogens, consisting of two functionally distinct components: the enzymatic “A” component for pathogenicity/cellular effects in host cells, and the receptor-binding “B” component for toxin delivery via a receptor-mediated endocytosis process. (B) Representative domain organizations of single-peptide AB toxins. DT, diphtheria toxin; CNF, cytotoxic necrotizing factor toxins; BoNT, botulinum neurotoxin; A, active or catalytic domain; R, receptor-binding domain; T, translocation domain; CNF can be further divided into five structural-building blocks D1–D5: D1–D2 for R domain, D3 for T domain, D4–D5 for A domain. BoNT A is also called BoNT light chain (LC, 50 kDa), while BoNT T and R domains are also called BoNT-heavy chain (HC, 100 kDa). (C) Representative subunit organizations of multiprotein AB toxins. CT, Cholera toxin; PT, Pertussis toxin; TyT, Typhoid toxin. TyT A1 and A2 indicate two separate enzymatic subunits, CdtB and PltA (see Fig. 2).

Fig. 2

Subtypes of multiprotein AB toxins. Multiprotein AB toxins can be further divided into various groups reflecting their A and B subunit stoichiometry found in their assembled holotoxins, such as AB₂, AB₅, A₂B₅, and A_(1–3)B₇. CDT, cytolethal distending toxin (PDB:1SR4). CT, cholera toxin (PDB:1S5E). TyT, typhoid toxin (PDB:4K6L). AnTx, Anthrax toxin (PDB:6ZXL).

Fig. 3

Bacterial ADP-ribosyltransferase toxins. (A) Bacterial ARTs transfer ADP-ribose from NAD⁺ onto a target protein in host cells. Unlike eukaryotic ARTs that often modify multiple protein targets and specifically modify arginine, bacterial ARTs typically target a single amino acid of a single protein with high specificity. Target amino acid residue is indicated with a red asterisk. (B) Bacterial ARTs are divided into two families, based on their amino acid residues important for their catalytic activity: bacterial RSE and HYE ARTs. DT, a HYE ART, targets a unique, post-translationally modified amino acid, diphthamide, found in eEF2 at residue 715. The RSE ARTs target a single amino acid residue on a single target protein that can be cysteine, arginine, threonine, glutamine, or asparagine depending on the toxin.

Fig. 4

Assembly and secretion of multiprotein AB toxins. (A) AB toxins are often encoded as one gene cluster or operon. Each subunit of multiprotein AB toxins is expressed as separate proteins in the bacterial cytoplasm, which possess an N-terminal signal peptide that makes each subunit individually cross the IM via the Sec system (indicated as an arrow symbol). In the periplasmic compartment, mature A and B subunit proteins are assembled, which often have multiple disulfide bonds to form. The assembled AB holotoxins are secreted from the bacteria to the extracellular environment via a protein secretion machinery(s) or a mechanism involving specific enzymes located on the bacterial membrane (indicated as an arrow symbol). CT, cholera toxin from V. cholerae. (B) AB toxin gene expression may require specific environmental cues, such as the vacuole environment in host cells (light brown; upper panel). TyT, typhoid toxin from S. Typhi (red rod-shaped symbol), which is in contrast to other AB toxins, including CT. Although the key concept for typhoid toxin gene expression, translocation, assembly, and secretion in bacteria is similar to other multi-protein AB toxins (lower panel), there are additional steps involved for TyT to be in the extracellular environment, including (i) invasion into host cells and (ii) translocation from the Salmonella-containing vacuole (SCV) to outside infected cells (upper left and right, respectively).

Fig. 5

Intracellular transport of AB toxins. AB toxins bind to a cell surface receptor (“U” shaped symbol in black or dark blue), which are specific glycans, proteins, or both. Receptor–toxin interactions initiate receptor-mediated endocytosis processes. During the vesicle trafficking processes, some AB toxins exit to the host cytoplasm from the endosome, while some exit from the ER. A subunit in the cytoplasm attacks a target protein, leading to cellular effects. Some A subunits, such as CdtB that attacks host DNA, further traffic to the nucleus in host cells. A, toxin A-component; B, toxin B-component; DT, diphtheria toxin; BoNT and TeNT, Clostridial neurotoxins; AnTx, anthrax toxin; ST, Shiga toxin; CT, cholera toxin; PT, pertussis toxin; TyT, typhoid toxin.