Which virulence factor of Pseudomonas aeruginosa is a heat-labile exotoxin that catalyzes ADP-ribosylation of elongation factor-2 (EF-2), leading to inhibition of protein synthesis?

Explanation

## Exotoxin A: The Major Virulence Factor of P. aeruginosa ### Mechanism of Action **Key Point:** Exotoxin A (also called Pseudomonas exotoxin or PE) is a potent A-B toxin that catalyzes ADP-ribosylation of elongation factor-2 (EF-2), permanently inactivating it and halting eukaryotic protein synthesis. ### Structural and Functional Features 1. **Structure:** A-B toxin (similar to diphtheria toxin) - Domain Ia: Catalytic domain (ADP-ribosyltransferase activity) - Domain II: Translocation domain - Domain III: Receptor-binding domain (binds to heparin-binding EGF-like growth factor precursor, HB-EGF) 2. **Mechanism:** - Binds to HB-EGF receptor on host cell surface - Undergoes receptor-mediated endocytosis - Translocates to cytoplasm in acidic endosome - Catalytic domain ADP-ribosylates EF-2 at diphthamide residue - EF-2 inactivation → protein synthesis cessation → cell death ### Clinical Significance **High-Yield:** Exotoxin A is: - The **most important virulence factor** in systemic P. aeruginosa infections - Responsible for tissue necrosis and systemic toxicity - Heat-labile (destroyed by heating to 56°C for 30 minutes) - Immunogenic — antibodies develop after infection - A target for vaccine development ### Comparison with Other P. aeruginosa Virulence Factors | Virulence Factor | Type | Function | Heat-Lability | |------------------|------|----------|----------------| | **Exotoxin A** | A-B toxin | ADP-ribosylates EF-2 | **Heat-labile** | | Exotoxin U (ExoU) | Phospholipase | Membrane disruption | Heat-stable | | Pyocyanin | Phenazine pigment | Oxidative stress, electron transport | Heat-stable | | LPS | Endotoxin | Inflammatory response | Heat-stable | | Type III secretion system toxins | ExoS, ExoT, ExoY | Actin disruption, cAMP elevation | Heat-stable | **Clinical Pearl:** Exotoxin A is particularly important in **acute invasive infections** (bacteremia, pneumonia, wound infections), while other virulence factors contribute to **chronic colonization** (especially in cystic fibrosis). **Mnemonic:** **EF-2 TOXIN** = **E**xotoxin A inactivates **E**longation **F**actor-**2** by ADP-ribosylation. [cite:Prescott's Microbiology 10e Ch 39]