Cholera toxin

**Organism:** Vibrio cholerae is a comma-shaped, gram-negative, oxidase-positive, motile rod with a single polar flagellum. It grows in alkaline media (TCBS agar, alkaline peptone water). Serogroups O1 (classical and El Tor biotypes) and O139 cause epidemics. Transmission is fecal-oral, through contaminated water or seafood (shellfish, plankton reservoirs). Stomach acid is a major defense, so the infectious dose is high, and hypochlorhydria (PPIs, antacids) raises risk.

**Toxin structure (AB5):** - A subunit (enzymatic): A1 is the active ADP-ribosyltransferase. A2 links A1 to the B pentamer. - B subunits (5): bind GM1 ganglioside on enterocytes, mediating endocytosis and retrograde trafficking to the ER. - The toxin genes (ctxAB) are carried on a lysogenic bacteriophage (CTXφ). Toxin-coregulated pilus (TCP) is the colonization factor and the phage receptor. Both are regulated by ToxR.

**Mechanism:** 1. The B pentamer binds GM1 on the enterocyte. 2. The A1 fragment is released into the cytosol. 3. A1 ADP-ribosylates the Gαs subunit. This inhibits its intrinsic GTPase activity, so Gαs stays locked in the GTP-bound "on" state. 4. Adenylyl cyclase is constitutively active, so cAMP rises. 5. PKA phosphorylates and opens CFTR (apical Cl- channel) in crypt cells. Cl- and water are secreted into the lumen, and Na+ follows. Na+ absorption via NHE is also inhibited in villus cells. 6. The result is massive isotonic secretory diarrhea.

**Clinical features:** - Sudden-onset, profuse, painless watery diarrhea ("rice-water" stools: flecks of mucus, no blood or WBCs). It can reach 1 L/hr. - Fishy odor. - Severe volume depletion: hypotension, tachycardia, sunken eyes, poor skin turgor, muscle cramps, oliguria or AKI. - Hypokalemia (stool K+ loss) and non-anion-gap metabolic acidosis (bicarbonate loss). - Hypoglycemia, especially in children. - No invasion of the intestinal mucosa, so the disease is purely toxin-mediated.

**Diagnosis:** Clinical in an endemic setting. Stool culture on TCBS (yellow colonies, sucrose fermenter) or rapid dark-field microscopy ("shooting star" motility). Rapid antigen tests are available.

**Treatment:** - Aggressive rehydration is the cornerstone: oral rehydration solution (ORS) or IV Ringer's lactate for severe cases. ORS works because Na+-glucose cotransport (SGLT1) is unaffected by the toxin. - Antibiotics shorten the course and reduce stool volume: doxycycline (adults), azithromycin (children, pregnancy), or a fluoroquinolone depending on resistance. - Mortality is high if untreated and low with prompt rehydration.

**Prevention:** Clean water and sanitation, oral cholera vaccine (killed whole-cell, or live-attenuated single dose in some regions).

**High-yield comparisons (toxins that raise cAMP):** - *E. coli* heat-labile toxin (LT): also ADP-ribosylates Gαs, causing traveler's diarrhea. It is similar to cholera toxin but milder. - *E. coli* heat-stable toxin (ST): activates guanylyl cyclase, raising cGMP. - Pertussis toxin: ADP-ribosylates Gαi, which disables inhibition of adenylyl cyclase, so cAMP also rises. - Mnemonic: cholera toxin keeps Gs "on" (Gs stuck on), while pertussis toxin keeps Gi "off." - Other ADP-ribosylating toxins: diphtheria toxin and *Pseudomonas* exotoxin A (inactivate EF-2), and botulinum C3 (rho). - Cholera is non-bloody and non-inflammatory. Compare with invasive pathogens (Shigella, Salmonella, Campylobacter, EIEC), which cause bloody or inflammatory diarrhea.

**Clinical pearl:** Think of cholera in a patient with sudden profuse watery diarrhea after travel to or exposure in an endemic area (e.g., Haiti, South Asia, sub-Saharan Africa) or after a natural disaster. It is also linked to raw or undercooked shellfish on the US Gulf Coast.