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AB toxin

AB toxins are a class of protein toxins produced by certain pathogenic bacteria and plants, characterized by a modular structure consisting of two distinct functional subunits: an enzymatically active A subunit that disrupts host cell processes and a receptor-binding B subunit that facilitates toxin delivery to target cells.^[1] The B subunit typically binds to specific carbohydrate receptors on the host cell surface, such as GM1 gangliosides or globotriaosylceramide (Gb3), triggering receptor-mediated endocytosis and subsequent translocation of the A subunit into the cytosol, where it exerts its toxic effects through mechanisms like ADP-ribosylation of proteins, inhibition of protein synthesis via ribosomal RNA depurination, or alteration of signaling pathways.^[2] This bipartite design enables precise targeting and potent cytotoxicity, contributing to diseases such as cholera, dysentery, and diphtheria.^[3] Structurally, AB toxins exhibit variations that enhance their efficiency and specificity; the B subunit often forms oligomeric structures, such as pentamers in cholera toxin (CTB) or heptamers/octamers in anthrax toxin protective antigen (PA), while the A subunit may be a single chain (as in diphtheria toxin) or cleaved into active fragments (e.g., A1 and A2 in Shiga toxin).^[1] Activation frequently involves proteolytic nicking and disulfide bond reduction, allowing the A subunit to unfold and translocate across membranes, either via short-trip endosomal pores in acidic conditions or long-trip retrograde transport through the Golgi and endoplasmic reticulum.^[3] Notable examples include cholera toxin from Vibrio cholerae, which ADP-ribosylates Gsα proteins to cause massive electrolyte secretion and diarrhea; Shiga toxin from Shigella dysenteriae and enterohemorrhagic Escherichia coli, which depurinates 28S rRNA to halt translation; and pertussis toxin from Bordetella pertussis, which modifies heterotrimeric G proteins to dysregulate immune responses.^[2] Plant-derived AB toxins like ricin from Ricinus communis follow similar principles, with its B chain binding galactose residues to enable A chain-mediated rRNA damage.^[1] Beyond their role in pathogenesis, AB toxins highlight evolutionary adaptations for host manipulation and have inspired biomedical applications due to their high-affinity binding and modular nature; for instance, non-toxic B subunits are engineered for targeted drug delivery in cancer therapy, exploiting overexpressed receptors like TEM8/CMG2 on tumor cells.^[2] Their study has elucidated key cellular trafficking pathways and enzymatic mechanisms, underscoring their significance in microbiology, toxicology, and therapeutic development.^[3]

Overview

Definition and Characteristics

AB toxins are a class of toxins produced by certain pathogenic bacteria and plants, composed of two functionally distinct subunits: the A subunit, which possesses enzymatic activity, and the B subunit, which is responsible for binding to host cell receptors and facilitating toxin delivery.^[4] These toxins are typically secreted as holotoxins in an inactive form and require proteolytic processing or environmental cues to activate the A subunit within the host cell.^[5] The A subunit catalyzes specific toxic reactions, such as ADP-ribosylation of host proteins or inhibition of protein synthesis, leading to disruption of cellular functions and pathogenesis.^[4] In contrast, the B subunit forms oligomeric structures, often pentamers, that recognize and bind to specific glycans or receptors on the target cell surface, enabling receptor-mediated endocytosis for intracellular translocation of the A subunit.^[4] A key characteristic of AB toxins is their reliance on this bipartite structure for targeted cytotoxicity, distinguishing them from other exotoxin types that act extracellularly or directly on membranes.^[5] Unlike type 1 superantigens, which non-specifically activate T cells by binding to MHC and T-cell receptors to induce massive cytokine release, AB toxins require internalization to exert their enzymatic effects inside the cell.^[5] Similarly, they differ from type 2 pore-forming or membrane-disrupting toxins, such as alpha-hemolysin from Staphylococcus aureus, which lyse cells by forming transmembrane pores without needing endocytosis.^[5] This receptor-dependent entry mechanism ensures high specificity and potency, often amplifying the toxin's impact at low concentrations.^[4] AB toxins are produced by a variety of pathogenic bacteria, including both Gram-positive and Gram-negative species, and by certain plants, contributing to diseases ranging from diarrhea to systemic infections and poisoning.^[4] Notable examples include cholera toxin from the Gram-negative Vibrio cholerae, diphtheria toxin from the Gram-positive Corynebacterium diphtheriae, Shiga toxin from the Gram-negative Shigella dysenteriae, and plant-derived examples like ricin from Ricinus communis.^[5] These toxins are secreted via specialized pathways, such as the type II secretion system in Gram-negative bacteria or direct export in Gram-positive ones, and their prevalence underscores their role as major virulence factors in bacterial pathogenesis.^[4]

Historical Background

The discovery of bacterial toxins as causative agents in infectious diseases marked a pivotal shift in microbiology during the late 19th century. In 1888, Émile Roux and Alexandre Yersin at the Institut Pasteur identified diphtheria toxin as a soluble substance produced by Corynebacterium diphtheriae, demonstrating its role in disease pathogenesis through experiments on guinea pigs where filtered bacterial cultures induced symptoms without live bacteria.^[6] Similarly, Robert Koch isolated Vibrio cholerae as the etiologic agent of cholera in 1883 during an outbreak in Egypt and India, confirming its transmissibility via contaminated water, though the toxin's specific contribution to symptoms remained unclear for decades.^[7] The role of cholera toxin was not elucidated until the mid-20th century, when Sambhu Nath De demonstrated in 1959 that cell-free filtrates from V. cholerae induced fluid secretion in rabbit ileal loops, establishing the toxin as the primary virulence factor.^[8] The 1970s brought significant advances in understanding toxin structures and mechanisms, laying the groundwork for the AB toxin paradigm. Richard A. Finkelstein and colleagues purified and characterized cholera toxin, revealing its oligomeric structure and subunits through biochemical techniques like gel filtration and electrophoresis.^[9] Alwin M. Pappenheimer Jr. contributed extensively to diphtheria toxin research, purifying the protein and elucidating its inhibition of protein synthesis in eukaryotic cells via ADP-ribosylation of elongation factor 2. Concurrently, D. Michael Gill demonstrated that cholera toxin activates adenylate cyclase by ADP-ribosylating the Gs alpha subunit of G proteins, providing a molecular basis for the toxin's diarrheagenic effects.^[10] In the 1980s, biochemical assays further confirmed the AB toxin model, where an enzymatic A subunit is delivered into cells by a receptor-binding B subunit, across multiple bacterial pathogens. Sjur Olsnes and collaborators advanced knowledge of protein translocation, showing how the A subunit of diphtheria toxin crosses endosomal membranes into the cytosol, a process involving low pH-induced conformational changes and pore formation.^[11] These studies, using techniques like reductive nicking and fluorescence spectroscopy, extended the model from diphtheria and cholera to toxins like pertussis and Shiga, solidifying the shared architecture.^[12] The classification of these agents evolved from ad hoc groupings in the 1970s—often termed "diphtheria-like" toxins based on shared enzymatic activities—to a formalized AB toxin category by the 1990s, encompassing structurally diverse but mechanistically analogous proteins from Gram-positive and Gram-negative bacteria. This framework, supported by comparative biochemical and genetic analyses, highlighted common themes in receptor binding, trafficking, and cytotoxicity, influencing subsequent research on toxin evolution and therapeutic targeting.^[13]

Molecular Structure

A Subunit

The A subunit of AB toxins is typically a single polypeptide chain with a molecular weight ranging from 20 to 30 kDa, comprising the enzymatic component responsible for intracellular toxicity.^[14] In cholera toxin, the A subunit is approximately 28 kDa and consists of two domains: the catalytic A1 domain (~23 kDa), which houses the active site for enzymatic modification, and the A2 domain (~5 kDa), an α-helical linker that facilitates association with the B subunit.^[15] Similarly, in diphtheria toxin, the catalytic A domain is a 21 kDa N-terminal fragment derived from a larger ~60 kDa precursor polypeptide.^[16] These structures often feature conserved motifs, such as the HYE triad in ADP-ribosyltransferase domains, enabling precise substrate recognition and catalysis.^[17] The primary function of the A subunit is to translocate into the host cell cytosol following delivery by the B subunit, where it catalyzes irreversible post-translational modifications of essential host proteins, thereby disrupting cellular processes.^[14] For instance, the A1 domain of cholera toxin acts as an ADP-ribosyltransferase, transferring the ADP-ribose moiety from NAD⁺ to the Gₛα subunit of heterotrimeric G-proteins, which constitutively activates adenylate cyclase and elevates cyclic AMP levels.^[14] In contrast, the A domain of diphtheria toxin also functions as an NAD⁺-dependent ADP-ribosyltransferase but targets diphthamide residue 715 on eukaryotic elongation factor 2 (EF-2), halting ribosomal translocation and inhibiting protein synthesis.^[16] These enzymatic activities are highly efficient, often requiring only a single A subunit molecule per cell to induce toxicity due to their catalytic turnover.^[17] Activation of the A subunit generally necessitates post-translational processing, including proteolytic cleavage and reduction of disulfide bonds, to liberate the active catalytic domain.^[14] In cholera toxin, furin-like proteases cleave the A subunit between A1 and A2 in the endoplasmic reticulum, with subsequent reduction of the interdomain disulfide bond (Cys-187 to Cys-199) by protein disulfide isomerase enabling A1 release into the cytosol.^[14] For diphtheria toxin, activation involves nicking at Arg-193 by furin proteases in early endosomes, separating the catalytic domain from the translocation and binding regions, followed by disulfide reduction (Cys-186 to Cys-201) to fully unleash enzymatic activity.^[16] This two-step activation ensures the A subunit remains dormant until intracellular delivery, preventing premature activity.^[17] The specificity of the A subunit is dictated by its active site architecture, which confers selectivity for particular host targets while exhibiting broad conservation across AB toxin families.^[17] Cholera toxin's A subunit precisely modifies Arg-201 on Gₛα, avoiding off-target ribosylation due to steric and charge complementarity in the enzyme-substrate complex.^[14] Diphtheria toxin's A domain, meanwhile, exclusively recognizes the modified histidine (diphthamide) on EF-2, a post-translationally modified residue essential for translational fidelity, rendering eukaryotic cells uniquely susceptible.^[16] Such targeted modifications underscore the A subunit's role as a precision disruptor of host physiology.^[17]

B Subunit

The B subunit of AB toxins is responsible for mediating the toxin's interaction with host cells, primarily through its structural architecture that supports receptor recognition and the delivery of the enzymatic A subunit. In many AB toxins, the B subunit adopts an oligomeric structure, often forming a pentameric ring in an AB5 arrangement, as seen in cholera toxin where five identical B subunits assemble into a doughnut-shaped homopentamer that encircles the A subunit, facilitating its passage through a central pore-like channel.^[18] Similarly, Shiga toxin features a pentameric B subunit that creates a stable ring structure essential for multivalent binding and A subunit protection.^[19] These oligomeric forms enhance stability and avidity, with molecular weights typically ranging from 7.7 kDa per monomer in Shiga toxin B to 11.6 kDa in cholera toxin B.^[4] The binding function of the B subunit confers specificity to AB toxins by recognizing particular glycolipid or glycoprotein receptors on target cell surfaces. For instance, the pentameric cholera toxin B subunit binds with high affinity to GM1 gangliosides, a ubiquitous sialic acid-containing glycosphingolipid, enabling selective attachment to intestinal epithelial cells.^[20] In contrast, Shiga toxin B subunits target globotriaosylceramide (Gb3) receptors, which are enriched on endothelial and renal cells, promoting tissue-specific tropism.^[21] This receptor interaction is multivalent in oligomeric B subunits, increasing binding strength through cooperative effects, as demonstrated by dissociation constants in the nanomolar range for cholera toxin B-GM1 complexes.^[22] Beyond binding, the B subunit plays a crucial delivery role by promoting endocytosis of the holotoxin and aiding in the safe transit of the A subunit, often exhibiting chaperone-like properties to shield it from degradation. In cholera toxin, the B pentamer induces lipid raft-mediated endocytosis and supports retrograde transport from endosomes to the Golgi apparatus, maintaining A subunit integrity during vesicular trafficking.^[23] Shiga toxin B similarly facilitates clathrin-independent uptake and protects the A subunit through its ring structure, which may sterically hinder premature proteolysis.^[24] These functions ensure efficient delivery without directly participating in A subunit activation. Structural variations in the B subunit across AB toxins reflect adaptations to different pathogens and host targets. While many are multimeric, such as the pentameric forms in cholera and Shiga toxins, others are monomeric, as in diphtheria toxin where the receptor-binding domain (approximately 17 kDa) is fused to the translocation domain within a single polypeptide chain.^[25] This monomeric configuration in diphtheria toxin binds heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursors, contrasting with the multimeric avidity of pentameric B subunits, yet still enables receptor-mediated entry.^[26] Such diversity underscores the evolutionary flexibility of B subunits in achieving toxin specificity and delivery efficiency.

Mechanism of Action

Binding and Entry

AB toxins initiate infection by the B subunit binding with high affinity to specific receptors on the host cell surface, a process that ensures targeted attachment. For instance, the B subunit of cholera toxin recognizes GM1 gangliosides on intestinal epithelial cells, while that of diphtheria toxin interacts with the heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursor on various cell types. This receptor recognition is mediated by multivalent interactions in oligomeric B subunits, such as the pentameric form in many AB toxins, which enhances binding avidity.^[4]^[27] Following receptor engagement, AB toxins are internalized via receptor-mediated endocytosis, which can involve clathrin-coated pits for many toxins (e.g., diphtheria toxin), while others like cholera toxin primarily utilize clathrin-independent pathways such as caveolae-mediated or lipid raft-associated endocytosis, depending on the cell type. The toxin-receptor complex is engulfed into early endosomes, where the acidic environment begins to influence the toxin's structure. This uptake mechanism is dynamin-dependent and allows the holotoxin to be transported intracellularly without immediate degradation.^[27]^[3] Within the endosome, the low pH (typically 5.0–6.0) triggers conformational rearrangements in the AB complex, promoting dissociation of the A and B subunits or formation of transmembrane pores. In diphtheria toxin, acidification induces the translocation domain to insert into the endosomal membrane, forming a channel that facilitates passage of the catalytic A subunit into the cytosol. Similar pH-driven changes occur in other AB toxins, optimizing the release of the active component while the B subunit remains associated with the receptor.^[4]^[27] The specificity of receptor binding and subsequent endocytosis determines the tissue tropism of AB toxins, restricting their effects to cells expressing the appropriate surface molecules. For example, the abundance of GM1 gangliosides on enterocytes confers intestinal tropism to cholera toxin, whereas widespread HB-EGF expression enables diphtheria toxin to affect multiple epithelial and immune cells. This selective targeting underlies the pathogens' ability to colonize particular host niches without broadly disseminating toxicity.^[4]^[3]

Intracellular Trafficking and Activation

Upon receptor-mediated endocytosis, AB toxins such as cholera toxin (CT) and diphtheria toxin (DT) are directed into early endosomes, from which they initiate retrograde transport to evade lysosomal degradation. This pathway involves trafficking through the trans-Golgi network (TGN) and Golgi apparatus to the endoplasmic reticulum (ER), utilizing host vesicular transport machinery. For CT, an AB5 toxin, this retrograde route exploits the ER-associated degradation (ERAD) pathway, where the holotoxin binds to ER-resident proteins like GRP78/BiP, facilitating its retention in the ER lumen.^[28] Similarly, DT follows a retrograde itinerary via the TGN and Golgi to the ER, as evidenced by electron microscopy studies showing toxin accumulation in these compartments.^[29] In the ER, the A subunit undergoes conformational changes necessary for translocation across the ER membrane into the cytosol. The A subunit typically unfolds, often assisted by ER chaperones such as protein disulfide isomerase (PDI), and translocates through the Sec61 translocon channel, mimicking misfolded proteins targeted for ERAD.^[28] Once in the cytosol, the A subunit refolds to restore its native structure and enzymatic potential; for CT, this involves PDI-mediated unfolding in the ER followed by cytosolic refolding.^[30] DT's A chain similarly translocates in a partially unfolded state via Sec61, refolding post-translocation to enable activity.^[31] Activation of the A subunit often requires proteolytic cleavage and reduction of disulfide bonds. In many AB toxins, furin-like proteases in the TGN or endosomes cleave the A subunit into A1 (catalytic) and A2 (translocation) fragments, linked by a disulfide bond; for example, Shiga toxin undergoes furin cleavage to generate the active A1 fragment.^[28] For CT and DT, reduction of this disulfide bond by thioredoxin reductase or PDI in the ER releases the active A1 fragment, priming it for cytosolic function.^[29]^[32] To reach the cytosol intact, AB toxins exploit host ubiquitination and ERAD pathways while evading proteasomal degradation. The unfolded A subunit engages ERAD components like E3 ubiquitin ligases but diverts the process toward translocation rather than ubiquitination and proteasomal destruction; CT, for instance, uses this hijacking to avoid degradation.^[28] DT similarly mimics ERAD substrates, binding to chaperones like Hsp90 to facilitate escape from ubiquitination, ensuring cytosolic delivery without breakdown.^[33] This evasion mechanism underscores the toxin's adaptation of host quality control systems for virulence.^[34]

Enzymatic Disruption

The A subunit of AB toxins, once translocated into the host cell cytosol, exerts its toxic effects through enzymatic modification of key cellular components, primarily acting as a catalyst to disrupt normal physiological processes.^[4] These enzymes typically employ post-translational modifications such as ADP-ribosylation, where the A subunit transfers an ADP-ribose moiety from NAD⁺ to specific target proteins, thereby altering their function.^[17] In some cases, such as with Shiga toxin, the A subunit functions as an N-glycosidase, cleaving a specific adenine residue from the 28S rRNA of the 60S ribosomal subunit, which inactivates ribosomes and halts protein synthesis. Common cellular targets include signaling proteins like the Gαs subunit of heterotrimeric G proteins, which cholera toxin's A subunit ADP-ribosylates at a glycine residue, locking it in a constitutively active state and leading to uncontrolled adenylate cyclase activation and cAMP elevation.^[35] Similarly, diphtheria toxin's A subunit ADP-ribosylates elongation factor 2 (EF-2) on its diphthamide residue, preventing the translocation step in protein synthesis and causing widespread translational arrest.^[36] These modifications result in ion channel dysregulation, persistent signaling imbalances, or blocked translation, ultimately compromising cellular homeostasis without directly damaging membranes.^[4] The enzymatic potency of the A subunit provides significant amplification, as a single molecule can catalytically modify thousands of substrate molecules due to its high turnover rate; for instance, one diphtheria toxin A fragment introduced into a cell is sufficient to inactivate all available EF-2, leading to cell lethality.^[36] This catalytic efficiency underscores the toxin's virulence, requiring only minimal cytosolic delivery to achieve profound effects.^[17] Prolonged enzymatic disruption triggers cell death pathways, including apoptosis triggered by protein synthesis inhibition, as seen with diphtheria and Shiga toxins, where ribosomal stress activates caspase cascades and DNA fragmentation.^[37] In cases of sustained signaling perturbation, such as elevated cAMP from cholera toxin, cells may progress to necrosis due to osmotic imbalance and energy depletion, though apoptosis predominates in translationally blocked scenarios.

Specific Examples

Cholera Toxin

Cholera toxin (CT), a prototypical AB5 toxin, is produced by toxigenic strains of the bacterium Vibrio cholerae serogroup O1 and occasionally O139. The toxin is encoded by the ctxA and ctxB genes, which are carried on the genome of the filamentous bacteriophage CTXφ. This phage integrates into the large chromosome (chrI) or small chromosome (chrII) of V. cholerae, enabling horizontal transfer of the toxin genes among bacterial populations. CTXφ acquisition is essential for the emergence of pathogenic strains, as non-toxigenic V. cholerae lack these genes and do not cause epidemic cholera.^[38]^[39] The structure of CT consists of a single A subunit (≈28 kDa) noncovalently associated with a pentameric ring of five identical B subunits (≈55 kDa total). The B pentamer binds with high affinity to the oligosaccharide portion of GM1 gangliosides on the surface of intestinal epithelial cells, facilitating toxin attachment and subsequent endocytosis. Once internalized, the A subunit is cleaved into A1 and A2 fragments; the enzymatically active A1 portion catalyzes the ADP-ribosylation of the arginine residue at position 201 on the stimulatory G protein subunit Gsα, using NAD⁺ as a substrate. This modification inhibits the intrinsic GTPase activity of Gsα, resulting in its permanent activation and constitutive stimulation of adenylate cyclase.^[40]^[41]^[42] The pathogenic effects of CT stem from this dysregulation of cellular signaling, leading to elevated intracellular cyclic AMP (cAMP) levels in enterocytes. High cAMP activates protein kinase A, which phosphorylates and opens the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels on the apical membrane, causing massive Cl⁻ efflux into the intestinal lumen. This anion secretion creates an osmotic gradient that drives passive Na⁺ and water efflux, resulting in the profuse, watery diarrhea characteristic of cholera, with fluid losses up to 20 liters per day in severe cases. Unlike invasive pathogens, CT does not damage the intestinal epithelium but exploits host ion transport mechanisms to induce secretory diarrhea.^[40]^[42]^[43] Variants of CT arise from differences in CTXφ genomes between V. cholerae biotypes, particularly classical and El Tor. Classical biotype strains produce CT with a specific nucleotide sequence in ctxB (ctxB1), while El Tor biotype strains encode a variant (ctxB7) with three amino acid differences that subtly alter toxin stability and immunogenicity. Classical CTXφ integrates as tandem prophages and does not excise to form infectious virions, limiting its spread, whereas El Tor CTXφ is lytic and produces transmissible particles, contributing to its environmental persistence. Evolutionary dynamics involve phage integration events, such as El Tor strains acquiring classical CTXφ, yielding hybrid "atypical El Tor" variants with enhanced virulence, as seen in seventh-pandemic strains. These phage-mediated exchanges drive the adaptation and global dissemination of toxigenic V. cholerae.^[38]^[39]^[44]

Diphtheria Toxin

Diphtheria toxin (DT) is a potent AB-type exotoxin produced by toxigenic strains of the Gram-positive bacterium Corynebacterium diphtheriae, which serves as a classic example of an AB toxin with systemic effects. The toxin is encoded by the tox gene, carried on a temperate bacteriophage such as β-corynephage, which lysogenizes the bacterial host. Expression of the tox gene is tightly regulated by iron availability through the diphtheria toxin repressor (DtxR) protein. DtxR represses tox transcription upon activation by Fe²⁺ binding under iron-replete conditions. Under iron-limiting conditions in the host during infection, when iron is scarce, the apo-DtxR form does not repress transcription, ensuring toxin production.^[45]^[46] Structurally, DT is synthesized as a single polypeptide chain of 535 amino acids, comprising an N-terminal catalytic A subunit (also called the C domain, residues 1–193) and a C-terminal B subunit (residues 194–535) linked by a disulfide bond, with the B subunit further divided into receptor-binding (R domain, residues 385–535) and transmembrane/translocation (T domain, residues 194–384) regions. The A subunit harbors the enzymatic active site for NAD⁺-dependent ADP-ribosylation, while the T domain features a bundle of hydrophobic α-helices (TH5–TH9), forming a "double-dagger" motif that facilitates membrane insertion and translocation of the A subunit into the cytosol following endocytosis. Unlike multimeric AB toxins such as cholera toxin, DT's single-chain architecture enables efficient unfolding and delivery of its catalytic domain.^[47]^[48]^[49] Upon entry into host cells via receptor-mediated endocytosis—binding to the heparin-binding epidermal growth factor-like growth factor (HB-EGF) precursor—DT undergoes low-pH-induced conformational changes in the endosome, allowing the T domain's hydrophobic helices to insert into the endosomal membrane and translocate the A subunit to the cytosol. There, the A subunit catalyzes the transfer of ADP-ribose from NAD⁺ to diphthamide, a unique histidine modification on elongation factor 2 (EF-2), irreversibly inactivating EF-2 and halting polypeptide translocation during protein synthesis. This enzymatic disruption leads to rapid cessation of translation, triggering apoptotic or necrotic cell death, with particular tropism for high-affinity target tissues such as the myocardium (causing myocarditis) and peripheral nerves (resulting in neuropathy). A single DT molecule can inactivate thousands of EF-2 molecules, amplifying its cytotoxicity.^[16]^[46]^[50] Not all C. diphtheriae strains produce DT; non-toxigenic variants lack the prophage or harbor mutations in the tox gene, leading to milder, localized infections without systemic toxicity, though they can still cause pharyngitis or wound infections. Immunity to DT is conferred by circulating antibodies that neutralize the toxin, typically acquired through vaccination with inactivated toxoid or prior exposure to toxigenic strains, preventing the toxin's pathogenic effects despite bacterial colonization.^[51]^[52]^[46]

Clinical Implications

Associated Diseases

AB toxins, produced by various bacterial pathogens, are responsible for a range of severe diseases through their disruption of host cellular functions. These toxins contribute to conditions characterized by high morbidity and mortality, particularly in vulnerable populations, and their impact is influenced by factors such as sanitation, vaccination coverage, and socioeconomic conditions.^[53]^[54] Cholera, caused by the AB5 toxin of Vibrio cholerae, remains endemic in regions with inadequate sanitation and clean water access, leading to widespread outbreaks during times of flooding or conflict. Globally, an estimated 1.3 to 4 million cases occur annually, with 21,000 to 143,000 deaths, primarily due to severe dehydration if untreated; reported cases reached 409,222 with 4,738 deaths from January to August 2025 across 31 countries.^[53]^[55]^[56] The disease's pathogenesis involves toxin-mediated ion secretion in the intestines, resulting in profuse watery diarrhea. Transmission occurs primarily through the fecal-oral route via contaminated water or food. Diphtheria, mediated by the diphtheria toxin (an AB toxin) from Corynebacterium diphtheriae, has seen a resurgence in unvaccinated or under-vaccinated populations, with notable outbreaks in the 2020s across African countries including Nigeria, Guinea, Niger, and Mauritania. The toxin's enzymatic activity inhibits protein synthesis in host cells, leading to local tissue necrosis and the formation of a characteristic grayish pseudomembrane in the throat, which can obstruct airways and cause systemic complications like myocarditis. This resurgence highlights gaps in routine immunization, with over 20,000 suspected cases reported across 8 African countries as of November 2025, building on tens of thousands of cases since 2023.^[57]^[54]^[58]^[59] Diphtheria spreads via respiratory droplets from infected individuals. Other AB toxins are linked to distinct syndromes, such as Shiga toxin from enterohemorrhagic Escherichia coli, which causes hemolytic uremic syndrome (HUS) through endothelial damage leading to microangiopathy, thrombocytopenia, and acute kidney injury, often following bloody diarrhea in children. Pertussis toxin from Bordetella pertussis underlies whooping cough, a respiratory illness marked by paroxysmal coughing and potential apnea in infants, with global resurgence due to waning vaccine immunity; for example, over 8,000 cases were reported in the United States by mid-2025.^[60]^[61]^[62] These enterotoxins, like those in cholera and Shiga toxin, typically transmit fecal-orally, while respiratory pathogens like diphtheria and pertussis rely on droplet spread.

Diagnosis and Treatment Strategies

Diagnosis of infections caused by AB toxin-producing bacteria typically involves a combination of microbiological culture, serological assays, and molecular techniques to confirm the presence of the pathogen and its toxin. For cholera, caused by Vibrio cholerae, the primary diagnostic method is the isolation and identification of the bacterium from stool specimens, followed by serogrouping for O1 or O139 antigens to confirm toxigenic strains.^[63] Polymerase chain reaction (PCR) assays targeting cholera toxin genes provide rapid detection, particularly useful in resource-limited settings during outbreaks.^[64] Enzyme-linked immunosorbent assay (ELISA) can detect cholera toxin directly in stool samples, offering high sensitivity for early identification.^[65] In diphtheria, diagnosis relies on clinical suspicion supported by throat or wound swabs cultured on selective media like Loeffler's serum slant to isolate Corynebacterium diphtheriae, with subsequent toxin production confirmed via Elek's test or PCR for the tox gene.^[51] For Shiga toxin-producing Escherichia coli (STEC) infections, stool culture on sorbitol-MacConkey agar identifies non-O157 strains, while PCR detects Shiga toxin genes (stx1 and stx2) for presumptive diagnosis, and ELISA confirms toxin presence.^[64] These methods ensure accurate identification, though confirmatory testing at reference laboratories, such as subtyping for cholera toxin, is recommended.^[65] Treatment strategies for AB toxin-mediated diseases prioritize rapid intervention to mitigate toxin effects and fluid loss. Cholera management focuses on aggressive rehydration, starting with oral rehydration solution (ORS) for mild cases and intravenous fluids for severe dehydration, which can reduce mortality from over 50% to less than 1%.^[53] Antibiotics such as doxycycline or azithromycin shorten diarrhea duration but are secondary to rehydration.^[66] For diphtheria, immediate administration of diphtheria antitoxin neutralizes circulating toxin, followed by antibiotics like penicillin or erythromycin to eradicate the bacteria and prevent transmission.^[54] In STEC infections, supportive care emphasizes hydration to prevent hemolytic uremic syndrome (HUS), with antibiotics contraindicated as they may increase toxin release and HUS risk.^[67] Challenges in managing AB toxin infections include delays in rapid diagnosis during outbreaks, where symptoms mimic other diarrheal illnesses, complicating timely intervention in endemic areas.^[68] Antibiotic resistance in V. cholerae, particularly to fluoroquinolones and tetracyclines, has emerged globally, driven by overuse and plasmid-mediated mechanisms, necessitating surveillance and alternative therapies like carbapenems.^[69] For diphtheria, limited antitoxin availability in low-resource settings poses additional hurdles.^[70] Supportive measures are integral to care, including strict isolation protocols to curb spread—such as contact precautions for diphtheria patients and enteric precautions for cholera cases—to prevent nosocomial transmission.^[71] Close monitoring for complications, particularly renal failure in STEC-associated HUS, involves serial assessment of renal function, electrolytes, and urine output, with dialysis initiated if acute kidney injury progresses.^[72] In severe diphtheria, cardiac and neurological monitoring addresses toxin-induced myocarditis or neuropathy.^[73]

Biomedical Applications

Vaccine Development

Vaccine development for AB toxins primarily revolves around toxoid-based approaches, where the toxin's enzymatic activity is inactivated while preserving its immunogenicity to elicit protective antibodies without causing disease. This strategy has been pivotal for several bacterial pathogens employing AB toxins, enabling safe immunization against toxin-mediated pathology. Seminal advancements include the creation of diphtheria toxoid in the early 1920s, which laid the foundation for routine childhood vaccination programs worldwide.^[74] The diphtheria toxoid vaccine, incorporated into the DTaP formulation (diphtheria and tetanus toxoids with acellular pertussis), demonstrates over 95% efficacy in preventing clinical disease following a primary series of three doses and boosters. It has been part of routine immunization schedules since the 1920s, dramatically reducing incidence from tens of thousands of cases annually in the early 20th century to near elimination in vaccinated populations. Similarly, the acellular pertussis vaccine includes a detoxified pertussis toxin (PT) toxoid as a key component, achieving 80-85% efficacy against pertussis disease in clinical trials when administered as DTaP. This vaccine replaced whole-cell versions in the 1990s to minimize side effects while maintaining protection through multiple doses up to adolescence.^[74]^[75] For cholera, oral vaccines like Dukoral combine the non-toxic B subunit of cholera toxin with killed whole-cell bacteria, providing 60-85% protection against moderate to severe disease for up to two years after two doses. This approach targets the toxin's binding mechanism while bolstering broader immunity, making it suitable for travelers and endemic settings. Shiga toxin vaccines are in advanced clinical development; for example, INM004, a mixture of monoclonal antibodies neutralizing Stx1 and Stx2, is in Phase 3 trials as of 2024 for treating or preventing hemolytic uremic syndrome in pediatric patients with Shiga toxin-producing E. coli (STEC) infections, building on preclinical and earlier clinical evidence of reduced toxin activity and HUS severity.^[76]^[77]^[78] Despite these successes, challenges persist in achieving and sustaining herd immunity, particularly in low-coverage regions where outbreaks recur due to suboptimal vaccination rates below 90%. Waning immunity necessitates boosters, especially for pertussis and diphtheria in adolescents and adults, while endemic areas for cholera require repeated campaigns to address gaps in access and infrastructure.^[54]^[79]

Immunotoxins and Targeted Therapies

Immunotoxins represent engineered fusion proteins that harness the cytotoxic potential of AB toxin subunits, particularly the enzymatic A subunits, by linking them to targeting moieties such as antibodies or ligands to selectively eliminate diseased cells, most notably in cancer therapy. A prominent example involves the truncated Pseudomonas exotoxin A (PE) fragment PE38, which lacks the native cell-binding domain and is fused to antibody fragments like single-chain variable fragments (scFv) or disulfide-stabilized Fv (dsFv) for tumor-specific delivery.^[80] This construct exploits PE's mechanism of ADP-ribosylating elongation factor-2 (eEF2) to inhibit protein synthesis and induce apoptosis in targeted cells.^[80] One FDA-approved immunotoxin, denileukin diftitox (also known as Lymphir or denileukin diftitox-cxdl), fuses the enzymatically active portion of diphtheria toxin (DT) with interleukin-2 (IL-2) to target IL-2 receptor-bearing cells, such as those in cutaneous T-cell lymphoma (CTCL); it received initial approval in 1999, full approval in 2008, and an updated biologics license in 2024 for relapsed or refractory Stage I-III CTCL after prior systemic therapy.^[81] In cancer targeting strategies, the non-toxic B subunits of AB toxins are often modified or repurposed to bind tumor-associated receptors, facilitating the delivery of cytotoxic A subunits or conjugated payloads directly to malignant cells while sparing healthy tissue. For instance, the B subunit of cholera toxin (CTB) binds GM1 gangliosides, which are overexpressed on certain tumor cells like those in small-cell lung carcinoma and hepatocellular carcinoma, enabling its use in nanoparticle-based drug delivery systems that enhance cellular uptake and trafficking for antitumor agents.^[27] Similarly, engineering the B subunit to recognize specific tumor receptors allows the A subunit to translocate and exert cytotoxicity, as seen in CT-based carriers that serve as both adjuvants and delivery vehicles for macromolecular therapeutics in cancer immunotherapy.^[82] These approaches leverage the natural trafficking pathways of AB toxins for precise intracellular delivery, improving therapeutic index over non-targeted chemotherapies.^[27] Recent advances have incorporated nanobodies—small, single-domain antibody fragments from camelids—into AB toxin fusions to enhance tumor penetration and specificity, particularly for solid tumors. A notable example is the αPD-L1-PE38 immunotoxin, which fuses an anti-PD-L1 nanobody to PE38 and demonstrates potent cytotoxicity against PD-L1-expressing tumors in vitro and in vivo, inducing apoptosis with minimal off-target effects when delivered via engineered bacteria.^[83] For glioblastoma, diphtheria toxin-derived short peptides have been developed to enable dual-targeted delivery of histone deacetylase inhibitors like vorinostat, exploiting the toxin's receptor-binding domain to cross the blood-brain barrier and selectively kill glioma cells, showing promise in preclinical models as of 2025.^[84] Clinical trials continue to evaluate such constructs, including PE-based immunotoxins like moxetumomab pasudotox (approved in 2018 for relapsed/refractory hairy cell leukemia but discontinued in 2023), with ongoing efforts in combination therapies for refractory solid tumors and hematologic malignancies into 2025.^[85]^[86] The primary advantages of these immunotoxins include their high specificity and potency, where fewer than 1,000 molecules per cell can induce tumor cell death, offering a targeted alternative to broad-spectrum agents.^[80] However, challenges persist, notably immunogenicity, where patients develop neutralizing antibodies in 11–88% of cases, limiting repeat dosing, and vascular leak syndrome (VLS), a dose-limiting toxicity causing capillary permeability and fluid shifts.^[80] Mitigation strategies, such as de-immunization through epitope mutations, domain deletions (e.g., PE domain II removal to eliminate VLS), and immunosuppressive pretreatments like pentostatin-cyclophosphamide, have improved tolerability and enabled multiple treatment cycles in clinical settings.^[87]

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