Clostridioides difficile toxin A

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Clostridioides difficile toxin A
Identifiers
Organism Clostridioides difficile
SymboltoxA
Alt. symbolstcdA
Entrez 4914076
RefSeq (Prot) YP_001087137.1
UniProt P16154
Other data
EC number 2.4.1.-
Chromosome genome: 0.79 - 0.81 Mb
Search for
Structures Swiss-model
Domains InterPro
SEM of Clostridioides difficile bacteria Clostridium difficile 01.jpg
SEM of Clostridioides difficile bacteria
PaLoc Reference: Clostridioides difficile strain 630, DSM 27543, genome GenBank accession number AM180355 Positions 770.154 to 789.973 bp, total locus size 19.8 kb. Archetypical Pathogenicity Locus (PaLoc),encoding the large clostridial toxins(LCTs) involved in C. difficile infections CDI.png
PaLoc Reference: Clostridioides difficile strain 630, DSM 27543, genome GenBank accession number AM180355 Positions 770.154 to 789.973 bp, total locus size 19.8 kb.

Clostridioides difficile toxin A (TcdA) is a toxin produced by the bacteria Clostridioides difficile , formerly known as Clostridium difficile. [1] It is similar to Clostridium difficile Toxin B. The toxins are the main virulence factors produced by the gram positive, anaerobic, [2] Clostridioides difficile bacteria. The toxins function by damaging the intestinal mucosa and cause the symptoms of C. difficile infection, including pseudomembranous colitis.

Contents

TcdA is one of the largest bacterial toxins known. With a molecular mass of 308 kDa, it is usually described as a potent enterotoxin, [3] but it also has some activity as a cytotoxin. [4] The toxin acts by modifying host cell GTPase proteins by glucosylation, leading to changes in cellular activities. Risk factors for C. difficile infection include antibiotic treatment, which can disrupt normal intestinal microbiota and lead to colonization of C. difficile bacteria. [5]

tcdA gene

The gene contains an open reading frame (ORF) of 8,133 nucleotides, coding for 2,710 amino acids. TcdA and TcdB share 63% homology in their amino acid sequences. [6] These genes are expressed during late log phase and stationary phase in response to environmental factors. Environmental stresses such as antibiotics and catabolite repression can influence toxin expression. [7]

Pathogenicity locus

The tcdA and tcdB genes are situated on the Clostridioides difficile chromosome in a 19.6-kb pathogenicity locus (PaLoc) found only in toxigenic strains of C. difficile. Non toxigenic strains contain a 127 base pair fragment replacing the PaLoc. [8] This locus also contains three other accessory genes tcdC, tcdR, and tcdE. [9] TcdC expression is high during early exponential phase and declines as growth moves into stationary phase, consistent with increases in tcdA and tcdB expression. Accordingly, expression patterns have indicated tcdC as a possible negative regulator of toxin production. tcdR may serve as a positive regulator of toxin production. [7] tcdE has been speculated to facilitate release of TcdA and TcdB through lytic activity on the bacterial cell membrane. Due to its homology with other proteins of similar function, as well as the location of the gene between tcdA and tcdB, tcdE is predicted to function as the lytic protein that facilitates release since TcdA and TcdB lack a signal peptide for secretion. [8]

Structure

The protein contains three domains. The amino N-terminal domain contains the active site, responsible for the glucosylating activity of the toxin. Both TcdA and TcdB use this highly conserved N-terminal region (74% homology between both toxins) to alter identical substrates. [7]

The carboxy C-terminal domain contains repeating units that are responsible for receptor binding on target cell surfaces. These short homologous repeating units have been termed combined repetitive oligopeptide (CROPs). [7] [10] A recent study demonstrates that the CROPs determine the potency of TcdA through interactions with structures on the cell surface. [11] These CROP regions range from 21-50 residues and play a role in receptor binding. [7] This C-terminal repetitive region is designated as the immuno-dominant region since ligand binding can be blocked by monoclonal antibodies specific to this region. [12] [13] This region contains the most hydrophilic portion of the molecule. [10]

A centrally located hydrophobic domain containing a cluster of 172 highly conserved hydrophobic amino acids is thought to be important for translocation of the enzymatic portion of the protein. [5] [6]

Mechanism of action

TcdA must be internalized into the host cell via endocytosis in order to access the cytosol. Receptor binding is the first step required for entry into the cell via endocytosis in an acidic endosome. [6] Low pH in the endosome induces structural changes such as exposure of the hydrophobic domains that are crucial for TcdA function. [7] [14]

The N-terminal domain of TcdA functions to catalyze a glucotransferase reaction, which transfers a glucose molecule from UDP-Glucose and covalently attaches it to conserved amino acids in target molecules. [6] Therefore, TcdA catalyzes glucosylation and the subsequent irreversible inactivation of target molecules in the Ras family of small GTPases. [9] These target molecules include RhoA, Rac, and Cdc42, which are regulatory proteins of the eukaryotic actin cytoskeleton and modulators of many various cell signaling pathways. [7]

Intracellular targets

TcdA primarily targets Rho, Rac, and Cdc42. These molecules are important regulators of cell signaling. Small GTPases such as Rho, Rac, and Cdc42 regulate their activity by alternating between an active GTP-bound state, and an inactive GDP-bound state. [7] Guanine exchange factors (GEFs) regulate the exchange of GTP and GDP. [15]

TcdA glucosylates RhoA by transferring a glucose molecule from UDP-glucose, a nucleotide sugar, to Thr-37 of the RhoA GTPase. In Rac and Cdc42, the sugar moiety is transferred to the Thr-35. The glucosylation prevents proper binding of GTP and blocks activation. [7] TcdA acts preferentially on the GDP-bound form of the GTPase proteins since this configuration exposes the threonine residue that is glucosylated by the toxin. [5]

RhoA regulates the actin cytoskeleton and forms stress fibers and focal adhesions. [16] When RhoA is inactivated via TcdA, its interaction with downstream effectors is inhibited. This leads to changes in the actin cytoskeleton that increase permeability of the intestinal epithelium. Rac and Cdc42 are involved in filopodium formation crucial for movement and cell migration. Overall, Rho, Rac, and Cdc42 all regulate processes in cells that are dependent on actin polymerization. Many of the physiologic effects that cells experience after exposure to TcdA can be linked to disregulation of actin polymerization and cellular pathways controlled by TcdA targets. [7]

Physiologic effects

Cell morphology

Exposure to TcdA leads to immediate changes in cell morphology, including loss of structural integrity due to a decrease in filamentous actin (F-actin), and an increase in globular actin. [17] Disorganization of actin filaments and the cytoskeleton leads to increased permeability of tight junctions resulting in severe epithelial cell damage and fluid secretion. [18] [19] Fluid accumulation and secretion are secondary to mucosal damage that occurs after exposure to TcdA. Distinct changes in the microfilament system lead to cell rounding and cell death. [17] These changes result from the inactivation of Rho proteins, which play an important role in regulating tight junctions. [7] [20]

Apoptosis

Apoptosis is the most likely mechanism accounting for death of cells exposed to TcdA. Rho inactivation can activate caspase-3 and caspase-9; two key components of the apoptotic pathway. TcdA has been linked to mitochondrial membrane disruption and release of cytochrome C through caspase activation and Rho inactivation, further suggesting that TcdA is capable of inducing apoptosis. [21] [22]

Clinical significance

Clostridioides difficile associated diarrhea (CDAD)

Animal models have shown TcdA includes diarrhea, neutrophil infiltration, inflammation of intestinal mucosa, and necrosis of epithelial cells. This toxin is considered the main cause of CDAD. [18] TcdA damages intestinal villous tips, which disrupts the brush border membrane, leading to cell erosion and fluid leakage from the damaged area. This damage and associated fluid response causes the diarrhea associated with Clostridioides difficile infection. [17]

Pseudomembranous colitis

TcdA can induce the physiological changes that occur in C. difficile related pseudomembranous colitis (PMC), a severe ulceration of the colon. Toxin damage to the colonic mucosa promotes accumulations of fibrin, mucin, and dead cells to form a layer of debris in the colon (pseudomembrane), causing an inflammatory response. [5] TcdA damage causes increased epithelial permeability, cytokine and chemokine production, neutrophil infiltration, production of reactive oxygen species (ROS), mast cell activation, and direct damage to the intestinal mucosa. [23] All can be attributed to TcdA induced inactivation of Rho GTPase proteins. [20] Loss of tight junctions can provide entry for neutrophils into the intestines, leading to neutrophil accumulation; a hallmark of PMC. TcdA induced cytokine production of IL-8 and other inflammatory mediators contributes to the stages of inflammation seen in PMC. Infiltration by neutrophils, macrophages, and mast cells in response to TcdA damage increases the inflammatory response through production and release of other mediators such as tumor necrosis factor alpha, IL-1, IL-6, and other monokines. These mediators cause additional damage to intestinal mucosa and further increase the inflammatory response, influencing PMC persistence. [24] If extensive damage to the intestinal wall occurs, bacteria can enter the bloodstream and cause septic shock and death. [5]

Toxin detection and diagnosis

TcdA and TcdB are present in supernatant fluids of C. difficile cultures and can be purified from filtrates. Both toxins are consistently detected in fecal samples from humans and animals [25] and are now used as markers to diagnose C. difficile infection. [7] Over 90% of patients infected with C. difficile were found to have cytotoxic activity in their stool. Glucosylation of Rho GTPases inactivates the GTPase proteins, leading to collapse of the cytoskeleton, resulting in cell rounding. A tissue culture assay has been developed to detect C. difficile toxins in stool samples. [17] A cell rounding assay (cytotoxicity assay) has been developed to diagnose C. difficile infection. [11] Enzyme-linked immunosorbent assays (ELISAs) have been used to detect TcdA and TcdB with specific antibodies. When used with an ELISA, the cytotoxicity assay is the "gold standard" when used on Vero cells for C. difficile diagnosis. [11]

Importance of TcdA and TcdB in C. difficile infection

Since the 1980s and early 1990s, the roles of TcdA and TcdB in C. difficile infection have been much debated. Previous reports with purified toxins indicated that TcdA alone was enough to cause symptoms of infection and TcdB was unable to do so unless combined with TcdA. [7] A more recent experiment indicated that TcdB was, in fact, essential for virulence. [26] Earlier research established TcdA strictly as an enterotoxin, and TcdB as a cytotoxin, but later both toxins were found to have the same mechanism of action. [6] To fully investigate the role of both toxins in pathogenesis of C. difficile infection, a gene knockout system in a hamster infection model was developed. By permanently knocking out tcdA, tcdB, or both (double knockout), it was shown that C. difficile producing one or both toxins was capable of cytotoxic activity, and this activity translated directly to virulence in vivo. It was also found that a double tcdAtcdB knockout was completely attenuated in virulence. Overall, this research has demonstrated the importance of both TcdA and TcdB in C. difficile infection, showing that either toxin is capable of cytotoxicity. [9]

See also

Related Research Articles

<i>Clostridioides difficile</i> infection Disease caused by C. difficile bacteria

Clostridioides difficile infection, also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

<span class="mw-page-title-main">Enterotoxin</span> Toxin from a microorganism affecting the intestines

An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines. They can be chromosomally or plasmid encoded. They are heat labile (>60⁰), of low molecular weight and water-soluble. Enterotoxins are frequently cytotoxic and kill cells by altering the apical membrane permeability of the mucosal (epithelial) cells of the intestinal wall. They are mostly pore-forming toxins, secreted by bacteria, that assemble to form pores in cell membranes. This causes the cells to die.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">RAC2</span> Protein-coding gene in the species Homo sapiens

Rac2 is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RAC2.

<span class="mw-page-title-main">RhoG</span> Protein-coding gene in the species Homo sapiens

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

<span class="mw-page-title-main">DEFA5</span> Mammalian protein found in Homo sapiens

Defensin, alpha 5 (DEFA5) also known as human alpha defensin 5 (HD5) is a protein that in humans is encoded by the DEFA5 gene. DEFA5 is expressed in the Paneth cells of the ileum.

Rac is a subfamily of the Rho family of GTPases, small signaling G proteins. Just as other G proteins, Rac acts as a molecular switch, remaining inactive while bound to GDP and activated once GEFs remove GDP, permitting GTP to bind. When bound to GTP, Rac is activated. In its activated state, Rac participates in the regulation of cell movement, through its involvement in structural changes to the actin Cytoskeleton. By changing the cytoskeletal dynamics within the cell, Rac-GTPases are able to facilitate the recruitment of neutrophils to the infected tissues, and to regulate degranulation of azurophil and integrin-dependent phagocytosis.

<i>Clostridioides difficile</i> toxin B Cytotoxin produced by Clostridioides difficile

Clostridioides difficile toxin B (TcdB) is a cytotoxin produced by the bacteria Clostridioides difficile. It is one of two major kinds of toxins produced by C. difficile, the other being a related enterotoxin. Both are very potent and lethal.

<span class="mw-page-title-main">AB toxin</span>

The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria, though there is a pore-forming AB toxin found in the eggs of a snail. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion. The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin.

Clostridium novyi (oedematiens) a Gram-positive, endospore- forming, obligate anaerobic bacteria of the class Clostridia. It is ubiquitous, being found in the soil and faeces. It is pathogenic, causing a wide variety of diseases in humans and animals.

<span class="mw-page-title-main">Fidaxomicin</span> Antibiotic

Fidaxomicin, sold under the brand name Dificid among others, is the first member of a class of narrow spectrum macrocyclic antibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenic Clostridioides difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridioides difficile infection.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

<span class="mw-page-title-main">Cytotoxic necrotising factor family</span>

In molecular biology, the cytotoxic necrotising factor family of proteins includes bacterial cytotoxic necrotising factor proteins and the related dermonecrotic toxin (DNT) from Bordetella species. Cytotoxic necrotizing factor 1 (CNF1) is a toxin whose structure from Escherichia coli revealed a 4-layer alpha/beta/beta/alpha structure containing mixed beta-sheets. CNF1 is expressed in strains of E. coli causing uropathogenic and neonatal meningitis. CNF1 alters host cell actin cytoskeleton and promotes bacterial invasion of the blood–brain barrier endothelial cells. CNF1 belongs to a unique group of large cytotoxins that cause constitutive activation of Rho guanosine triphosphatases (GTPases), which are key regulators of the actin cytoskeleton.

Bezlotoxumab, sold under the brand name Zinplava, is a human monoclonal antibody designed for the prevention of recurrence of Clostridioides difficile infections.

<i>Clostridioides difficile</i> Species of bacteria

Clostridioides difficile is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as C. difficile, or C. diff, and is a Gram-positive species of spore-forming bacteria. Clostridioides spp. are anaerobic, motile bacteria, ubiquitous in nature and especially prevalent in soil. Its vegetative cells are rod-shaped, pleomorphic, and occur in pairs or short chains. Under the microscope, they appear as long, irregular cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. C. difficile is catalase- and superoxide dismutase-negative, and produces up to three types of toxins: enterotoxin A, cytotoxin B and Clostridioides difficile transferase. Under stress conditions, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.

The Clostridial Cytotoxin (CCT) Family is a member of the RTX-toxin superfamily. There are currently 13 classified members belonging to the CCT family. A representative list of these proteins is available in the Transporter Classification Database. Homologues are found in a variety of Gram-positive and Gram-negative bacteria.

<span class="mw-page-title-main">Ridinilazole</span> Chemical compound

Ridinilazole is an investigational small molecule antibiotic being evaluated for oral administration to treat Clostridioides difficile infection (CDI). In vitro, it is bactericidal against C. difficile and suppresses bacterial toxin production; the mechanism of action is thought to involve inhibition of cell division. It has properties which are desirable for the treatment of CDI, namely that it is a narrow-spectrum antibiotic which exhibits activity against C. difficile while having little impact on other normal intestinal flora and that it is only minimally absorbed systemically after oral administration. At the time ridinilazole was developed, there were only three antibiotics in use for treating CDI: vancomycin, fidaxomicin, and metronidazole. The recurrence rate of CDI is high, which has spurred research into other treatment options with the aim to reduce the rate of recurrence.

The Clostridium difficile TcdE Holin Family is a group of transporters belonging to the Holin Superfamily IV. A representative list of its members can be found in the Transporter Classification Database.

References

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  25. ↑ Lima AA, Lyerly DM, Wilkins TD, Innes DJ, Guerrant RL (March 1988). "Effects of Clostridium difficile toxins A and B in rabbit small and large intestine in vivo and on cultured cells in vitro". Infection and Immunity. 56 (3): 582–8. doi:10.1128/IAI.56.3.582-588.1988. PMC   259330 . PMID   3343050.
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