Lethal factor
Summary
Lethal factor is one of three components of anthrax toxin produced by Bacillus anthracis, acting as a zinc-dependent metalloprotease that cleaves MAPKK (MEK) proteins. Combined with protective antigen, it disrupts cell signaling, leading to cell death, particularly in macrophages, contributing to tissue necrosis and edema seen in anthrax infection.
Detail
Bacillus anthracis produces a tripartite exotoxin consisting of protective antigen (PA), edema factor (EF), and lethal factor (LF). Protective antigen binds to host cell receptors and forms a pore allowing EF and LF to enter the cytosol. Lethal factor is a zinc-dependent metalloproteinase that cleaves mitogen-activated protein kinase kinases (MAPKKs/MEKs), disrupting intracellular signaling pathways essential for cell survival and immune response. This leads to macrophage dysfunction, release of pro-inflammatory cytokines, and ultimately macrophage lysis, contributing to the systemic toxicity, tissue necrosis, and hemorrhage characteristic of anthrax, especially in the lethal inhalational form. Edema factor, by contrast, is a calmodulin-dependent adenylate cyclase that increases cAMP levels, causing edema. Together, lethal toxin (PA+LF) and edema toxin (PA+EF) are responsible for the clinical manifestations of anthrax including widened mediastinum on chest X-ray (inhalational anthrax), hemorrhagic lymphadenitis, and potential septic shock. Anthrax is caused by a gram-positive, spore-forming rod with a polypeptide (poly-D-glutamate) capsule that inhibits phagocytosis. Vaccination targets protective antigen. Clinically relevant for bioterrorism preparedness and understanding toxin-mediated pathogenesis in microbiology coursework.
Sources
- First Aid for the USMLE Step 1
- Sherris Medical Microbiology
- Harrison's Principles of Internal Medicine
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