(9/02/10) - Endocytosis and Pathogens: Anthrax



Endocytosis and Pathogen Entry: Anthrax

Molly A. Hughes, MD PhD

Division of Infectious Diseases

1. Describe the two forms of Bacillus anthracis, the pathogen that causes the disease known as anthrax.

Spore – the infection agent of anthrax; consists of nucleic acid surrounded by a highly structured protective casing; highly resistant to drying, heat, UV light, gamma radiation & many disinfectants; exist in soils, animal hair (wool), and hides.

Bacillus – responsible for disease (septicemia, toxemia); produces a tripartite toxin involved in immune suppression (pXO1); produces an anti-phagocytic capsule (pXO2)

2. List the three major clinical forms of anthrax.


 * Pulmonary – spore-laden dust


 * Gastrointestinal – infected meat, contaminated water (?)


 * Cutaneous – via lesion

3. Describe the major virulence factors of Bacillus anthracis.


 * pXO1 – genes that code protective antigen (PA), lethal factor (LF), and edema factor (EF)


 * PA+LF = Lethal toxin (cell & organism death; MAPK kinase cleavage)


 * PA+EF = Edema toxin (increases cAMP levels)


 * PA is required to get into the host cell, but LF and EF both have enzymatic activity on their own. PA is normally 83 kD, but it is cleaved to 63 kD by the host cell.


 * pXO2 – genes that encode the capsule that is antiphagocytic.

4. Describe how the anthrax toxins are taken up by host cells and how they can cause disease.

TEM8 (tumor endosomal marker) and ATR (anthrax toxin receptor) receptors bind PA, furin cleaves PA and the receptors form a heptomer. EF or LF can then bind to PA (3 EF/LF to 7 PA), and then endocytosis occurs. After acidification, PA binds to the membrane to form a pore, allowing for the translocation of the EF or LF into the cytoplasm. These are released into the bloodstream and taken up in other cells.

5. Describe the major clinical forms of anthrax and how the infection can occur (with specific focus on pathogen entry, toxin production and uptake by host cells).


 * Cutaneous – 95%; papule forms in 1-2 days. Changes to vesicle that ruptures to form elcer and eventual black eschar. Hands, head and neck are most frequently involved. Painless, lasts 2-3 weeks. Edema most pronounced on face.


 * Gastrointestinal – symptoms 2-5 days after ingestion of spores; severe abdominal pain, vomiting of blood, bloody diarrhea or constipation and shock; rare, but very deadly.


 * Pulmonary – incubation period average 9 days (2-43); fever, cough, and weakness initially; chest x-ray shows mediastinal widening and pleural effusions; shock and meningitis/meningoencephalitis; mortality 86%; not contagious person-to-person.

Other

Once the bacteria have secreted a large amount of toxins, treatment with antibiotics is ineffective; strategies are needed to prevent or disrupt the uptake or biological activities of the toxins.

For more information, see: Dixon et al. (1999) NEJM 341:815-826