A 45-year-old man who works in a sheep wool processing facility is brought to the emergency department with a rapidly progressing illness characterized by high fever, severe dyspnea, and retrosternal chest pain. A chest radiograph reveals a significantly widened mediastinum and bilateral pleural effusions. Blood cultures subsequently grow large, Gram-positive, spore-forming rods in chains. The rapid clinical deterioration seen in this patient is largely mediated by a tripartite exotoxin.
Arrange the following cellular events in the correct chronological sequence regarding the cellular entry and activation of this pathogen's primary virulence complex.
- 1Binding of the protective antigen (PA) to host cell surface receptors and subsequent enzymatic cleavage by host furin.
- 2Assembly of cleaved protective antigen monomers into a heptameric prepore structure on the cell membrane.
- 3Binding of the catalytic toxins, edema factor (EF) and lethal factor (LF), to the assembled prepore complex.
- 4Endocytosis of the fully assembled toxin-receptor complex into an intracellular vesicle.
- 5Acidification of the endocytic vesicle, driving a conformational change that translocates the catalytic components into the cytosol.
Answer
The correct sequence begins with the binding and cleavage of protective antigen (PA), followed by its assembly into a heptameric prepore. Next, edema factor and lethal factor bind to the prepore on the cell surface. The assembled complex is then endocytosed, and finally, endosomal acidification triggers pore formation and cytosolic translocation of the toxins.
The pathogenesis of Bacillus anthracis depends on a tripartite exotoxin consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF), and its cellular entry is strictly sequential. First, PA binds to host cell receptors (such as TEM8 or CMG2) and is cleaved by host furin to expose an oligomerization site. Second, cleaved PA monomers assemble into a heptameric prepore. Third, EF and LF bind competitively to this prepore on the outer cell surface. Fourth, the complete tripartite complex is internalized via clathrin-mediated endocytosis. Finally, the acidic pH within the maturing endosome causes a conformational change in the prepore, allowing it to pierce the endosomal membrane and translocate EF and LF into the host cell cytosol where they exert their toxic effects (increasing cAMP and cleaving MAP kinase kinases, respectively).
Step-by-Step Solution
Key Concept
Pathogenesis of Bacillus anthracis tripartite exotoxin internalization