A 65-year-old woman is evaluated in the hospital for severe, watery diarrhea and abdominal cramps. She recently completed a 10-day course of clindamycin for a dental infection. Flexible sigmoidoscopy reveals raised, yellowish plaques on the colonic mucosa. The pathogenesis of this patient's condition involves a specific sequence of pathophysiological events.
Arrange the following steps in the pathogenesis of this infection in the correct chronological order, from the initial predisposing event to the final cellular effect.
- 1Disruption of the normal protective colonic microbiota by antimicrobial therapy
- 2Germination of bacterial spores into actively dividing vegetative cells
- 3Secretion of multimodular exotoxins (Toxin A and Toxin B)
- 4Cellular internalization and glucosylation of Rho family GTPases
- 5Disruption of the actin cytoskeleton leading to colonocyte apoptosis
Cevap
The correct sequence begins with antibiotic-induced disruption of the normal flora, followed by spore germination, toxin secretion, intracellular glucosylation of Rho GTPases, and ultimately cytoskeletal disruption.
The pathogenesis of Clostridioides difficile pseudomembranous colitis follows a strict sequential cascade. It begins when broad-spectrum antibiotics (like clindamycin) suppress the normal colonic microbiome. This allows ingested or endogenous C. difficile spores to germinate into vegetative bacteria. These vegetative cells then proliferate and secrete Toxin A and Toxin B. The toxins bind to host cell receptors, undergo endocytosis, and translocate their active domains into the cytosol. There, they catalyze the transfer of a glucose moiety to Rho family GTPases. This glucosylation inactivates the GTPases, preventing them from maintaining the actin cytoskeleton, which ultimately leads to cell rounding, apoptosis, mucosal inflammation, and the exudative pseudomembranes characteristic of the disease.
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Anahtar Kavram
Pathogenesis and cellular mechanism of Clostridioides difficile infection