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Difficulty: HardInfectious Disease Mechanisms

A 62-year-old woman comes to the urgent care clinic complaining of profuse, watery, foul-smelling diarrhea for the past 4 days. She reports having up to 8 bowel movements a day, accompanied by lower abdominal cramping and a low-grade fever. Ten days ago, she was discharged from the hospital after a 5-day admission for community-acquired pneumonia, for which she completed a course of levofloxacin. Her temperature is 38.1°C (100.6°F), pulse is 105/min, and blood pressure is 110/70 mm Hg. Physical examination reveals a mildly distended abdomen with diffuse tenderness but no rebound or guarding. Laboratory studies show a leukocyte count of 18,000/mm³. Stool enzyme immunoassay is positive for a bacterial exotoxin. Which of the following best describes the primary intracellular mechanism of the exotoxin responsible for this patient's gastrointestinal findings?

  1. Inactivation of host cell Rho GTPases via glycosylationAnswer
  2. B
    ADP-ribosylation of the stimulatory G-protein alpha subunit (GsG_s)
  3. C
    Cleavage of the 28S rRNA of the 60S ribosomal subunit
  4. D
    Enzymatic degradation of membrane phospholipids via lecithinase activity
  5. E
    Proteolytic cleavage of SNARE proteins preventing vesicular fusion

Answer

Inactivation of host cell Rho GTPases via glycosylation
The patient's clinical presentation of watery diarrhea, fever, abdominal cramping, and marked leukocytosis following recent antibiotic use (levofloxacin) is highly characteristic of Clostridioides difficile infection. Pathogenesis is mediated by two primary exotoxins: Toxin A and Toxin B. Once endocytosed by colonic epithelial cells, these toxins act as UDP-glucosyltransferases. They transfer a glucose molecule to (glycosylate) small GTP-binding proteins of the Rho family (Rho, Rac, and Cdc42), inactivating them. Because these GTPases are essential for maintaining the actin cytoskeleton, their inactivation leads to actin depolymerization, disruption of intercellular tight junctions (causing increased mucosal permeability and watery diarrhea), and eventual enterocyte apoptosis.

Step-by-Step Solution

1
Analyze the patient's clinical presentation and history.
The patient has profuse watery diarrhea, fever, leukocytosis, and a recent history of hospitalization with fluoroquinolone (levofloxacin) use.
Identifying the classic risk factors (recent antibiotic use, hospitalization) narrows the differential diagnosis to antibiotic-associated colitis.
2
Identify the most likely causative organism.
Clostridioides difficile is the most common cause of post-antibiotic diarrhea and pseudomembranous colitis.
Antibiotics disrupt the normal colonic flora, allowing for the overgrowth of C. difficile and the subsequent production of exotoxins.
3
Determine the molecular mechanism of the pathogen's virulence factors.
C. difficile produces Toxin A (enterotoxin) and Toxin B (cytotoxin). Both toxins act by glucosylating (a type of glycosylation) Rho family GTPases.
The question specifically asks for the primary intracellular mechanism of the exotoxin responsible for the pathogenesis.

Key Concept

The primary virulence factors of Clostridioides difficile are Toxins A and B, which cause colonic mucosal injury and inflammation by glucosylating and inactivating host cell Rho GTPases, leading to actin cytoskeletal disruption.
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Topics

Infectious Disease Mechanisms

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