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Difficulty: MediumInfectious Disease Mechanisms

A 4-year-old girl is brought to the pediatric urgent care clinic by her parents due to a two-day history of bloody diarrhea, severe abdominal cramping, and low-grade fever. The family recently visited a local dairy farm. Laboratory tests reveal microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Stool culture isolates a Gram-negative bacillus that ferments lactose but does not ferment sorbitol. The primary virulence factor responsible for this patient's systemic complications causes cellular damage through which of the following molecular mechanisms?

  1. A
    ADP-ribosylation of elongation factor-2 to halt polypeptide chain elongation
  2. B
    Constitutive activation of adenylate cyclase leading to a massive efflux of chloride and water
  3. Removal of a specific adenine base from the 28S ribosomal RNA of the 60S subunitAnswer
  4. D
    Zinc metalloprotease cleavage of SNARE proteins to inhibit vesicular fusion
  5. E
    Hydrolysis of host cell membrane lecithin resulting in extensive cellular lysis

Answer

Removal of a specific adenine base from the 28S ribosomal RNA of the 60S subunit
The patient's presentation of bloody diarrhea followed by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury is classic for Hemolytic Uremic Syndrome (HUS). The stool culture isolation of a Gram-negative bacillus that ferments lactose but fails to ferment sorbitol confirms the diagnosis of Enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection. EHEC causes systemic damage primarily through the elaboration of Shiga-like toxin (Verotoxin). Once inside the host endothelial cells, the A subunit of this toxin acts as an RNA N-glycosidase. It specifically removes a single adenine base from the 28S ribosomal RNA of the 60S ribosomal subunit. This depurination prevents the binding of aminoacyl-tRNA to the ribosome, irreversibly halting protein synthesis and leading to endothelial cell death. This endothelial damage initiates the widespread microthrombi formation characteristic of HUS.

Step-by-Step Solution

1
Identify the clinical syndrome and likely pathogen from the patient's presentation.
The combination of bloody diarrhea followed by hemolytic anemia, thrombocytopenia, and acute kidney injury indicates Hemolytic Uremic Syndrome (HUS). The stool culture finding of a lactose-fermenting, sorbitol-non-fermenting Gram-negative bacillus identifies Enterohemorrhagic Escherichia coli (EHEC) O157:H7.
Correctly identifying the pathogen is required to determine the specific virulence factor involved.
2
Identify the primary virulence factor produced by EHEC that causes systemic complications.
EHEC produces Shiga-like toxin (Verotoxin), which enters the bloodstream and damages the endothelium, leading to HUS.
The severe systemic complications (HUS) are toxin-mediated rather than being caused by bacterial invasion of the bloodstream.
3
Recall the precise molecular mechanism of Shiga-like toxin.
The A subunit of Shiga-like toxin acts as an N-glycosidase, cleaving a specific adenine residue from the 28S rRNA of the host's 60S ribosomal subunit.
This enzymatic action prevents the binding of aminoacyl-tRNA, irreversibly halting host protein synthesis and causing endothelial cell death.

Key Concept

Enterohemorrhagic Escherichia coli (EHEC) produces Shiga-like toxin, which causes Hemolytic Uremic Syndrome (HUS) by inactivating the 60S ribosomal subunit through the removal of a specific adenine residue from the 28S rRNA, halting host cell protein synthesis.
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Infectious Disease Mechanisms

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