MMI 301 Lecture 15- Anthrax

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MMI 301 Lecture 15- Anthrax
2013-11-01 10:43:02
MMI 301

MMI 301
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  1. Anthrax host
    Herbivores, mostly sheep and cattle
  2. Anthrax History
    • First target of Koch's Postulates by Koch
    • First target of vaccination- Pasteur
    • Been a recognized disease since ancient times
    • Name from greek anthrakas (coal) due to black wound in cutaneous disease
  3. Bacillus anthrax morphology
    • Gram + Large rods
    • Forms endospores
    • Found in soil
    • Vegetative form encapsulated
    • Non-motile
    • Facultative anaerobe
  4. Endospores
    • Can survive decades in environment
    • Core contains dipicolinic acid, DNA and ribosomes
    • Cortexis made of peptidoglycan
    • Exosporium coat of mostly glycoproteins
    • Endospores are metabolically inactive
  5. Formation of Endospore
    • 1. Spore septum isolates replicate DNA in cell
    • 2. Cell membrane begins to isolate, septum closes
    • 3. Forespore forms with two layers
    • 4. Peptidoglycan layer forms between cell membrane and spore septum
    • 5. Spore coat formed
    • 6. Spore released
  6. Component/purpose of Anthrax capsule/S-layer
    • Capsule: polymer of D-glutamic acid (not carb)
    • -Anti-phagocytic
    • S-layer: paracrystalline layer of protein.
    • -unknown, maybe evade complement, create periplasmic-like space, filter macromolecules
  7. Diseases associated with Anthrax
    • Cutaneous anthrax
    • Gastrointestinal anthrax
    • Inhalation anthrax (bioweapon)
  8. Cutaneous Anthrax
    • Woolsorter's disease
    • Endospores enter through abrasion/bite
    • 3-5 days after infection, papule forms
    • Progresses to necrotic lesion
    • Black eschar surrounded by vesicles/edema
    • Occupational Hazard
    •     -Contracted from wool/hide/animal related
  9. Cutaneous Anthrax Treatment
    • Easily treated with antibiotics
    • Most common infection
    • Can become bloodborne/systemic
  10. Gastrointestinal Anthrax
    • Not in US
    • From contaminated meat
    • Ulceration of GI tract
    • 100% lethal if untreated
  11. Inhaled Anthrax
    • Inhalation of endospores into alvelolar space
    • Spreads to mediastinal lymph nodes, then to body
    • Almost always fatal
    • Contaminated soil/animal
    • Bioweapon
  12. Inhaled Anthrax Pathogenesis
    • Spores taken by macrophages to lymph nodes
    • Spores germinate in macrophages
    • Bacteria escape and infect blood
    •     -Use edema toxin EdTx and lethal toxin LeTx
  13. Anthrax virulence factors
    • pXO2 plasmid encodes for capsule gene
    • pXO1 plasmid encodes for two exotoxins
    • These plasmids separate anthrax from other B. cereus
  14. Anthrax Capsule as Virulence Factor
    • Made of poly-y-glutamic acid
    • Made up of D-amino acid monomers
    • Is weakly immunogenic
    • Genes found in pXO2
    • Strains cured of pXO2 are slightly attenuated
  15. AB Toxins as a Virulence toxin
    • Both toxins consist of protective antigen+other factor
    • Neither component is toxic alone
    • Edema toxin:
    •     -Alters water homeostasis, resulting in edema (massive influx of fluid to area, inhibiting neutrophil action)
    • Zinc Protease:
    •      -Lethal toxin, cleaves proteins, causes macrophages to release proinflammatory cytokines TNF-alpha and IL-1beta
    •       -Toxin shock
  16. Edema Factor (EF)
    • Encoded by cya gene on pXO1
    • Calmodulin-dependent adenylate cyclase (like pertussis)
    • Non-lethal, causes edema
    • Inhibits phagocytosis by immune cells
    •    -Impairs oxidative burst of neutrophils
  17. Lethal Factor (LF)
    • Encoded by lef gene on PXO1
    • Zinc metalloprotease
    • Cleaves MAP kinase kinase
    •    -impairs intracellular signalling
    • Only kills macrophages, unknown mechanism
    • Mode of action:
    •       -Production of ROS
    •       -Production of IL-1, TNF-alpha
  18. Protective Antigen (PA)
    • encoded by pagA genes on pXO1
    • Heptameric four-domain protein
    • Host-mediated proteolysis follows receptor binding:
    •     -Removes amino acids, exposes binding site for EF/LF
    •    -Exposed site then binds
  19. Anthrax and Biowarfare
    • WWI: German agents infected neutral country livestock being sent to allies
    • Late 1930's: Japanese Imperial Army deploys anthrax in Manchuria
    • WWII: Canada/UK/US develop anthrax bomb
    • 1972: Biological Weapons Convention bans all things related to bioweapons
    • 1979: Accidental release of spores from bioweapon plant kills 75 Russians
    • 1988: Soviets transport 100 tons of anthrax spores to an island. 11 years later, still good
    • 1998: Iraq admits to have produced 2000 liters of spores in gulf war
    • US/Russia+13 other countries believed to have anthrax
  20. Sverdlovsk Incident
    • 1979: 120-400+ ill, '75' dead.
    • Soviets initially reported it to be contaminated meat, hemorrhagic mediastinitis found
    • Disease linked to aerosol leak from weapons plant.
  21. Anthrax in 9/11
    • Beginning Sept. 18th anthrax was mailed to US news media/congressmen FBI concluded it was Dr. Bruce Irvins, scientist at USAMRID
    • 22 infected (5 dead), victims where mail-handlers
  22. Anthrax Vaccine
    US uses PA from culture filtrate of an avirulent, nonencapsulated form.
  23. Surface Proteins of Gram + bacterias
    • LPXTG protein
    • Hydrophobic tail protein
    • GW protein
    • Lipoprotein
  24. Sortase
    • Transamidase
    • Covalently attaches proteins with LPxTG motif to cell wall
    • This is how pilus are assembled in anthrax
    • Also attaches some iron acquisition proteins  (Hal)
  25. Important Factoids
    • Anthrax forms endospores
    • Cause 3 types of diseases
    • AB (lethal and edema toxins)
    • Anthrax is bioweapon since WWI
    • Gram positive bacteria use sortases to attach proteins