Transcript
Anthrax
MIlad khourySpring 2011
ARTICLE
“New medical weapons to protect against Anthrax attacks”
Bouzianas et al. Current and Future Medical Approaches To Combat the Anthrax Threat. Journal of Medicinal Chemistry, 2010; 53 (11): 4305 DOI: 10.1021/jm901024b
Outline
I Introduction
II History of the disease
III Its use as a biological weapons
IV Bacillus anthracis
V the 3 routs of inection
VI Pathogenesis
VII The fight against anthrax
VIII Conclusion
Anthrax: basics From the Greek word anthracis for coal. caused by the bacteria B.anthracis Zoonotic disease in herbivores (e.g., sheep, goats,
cattle) Human infection typically acquired through contact
with anthrax-infected animals or animal products . Three forms
-Cutaneous
-Inhalational
-Gastrointestinal
history
1500 B.C
Moses threatened the Egyptian pharaoh that the hand of the lord will fall on the livestock ,horses and birds and kill everything.
5th century B.C
the Greek Doctor Hippocrates named the disease that caused black skin lesions as anthracis.
history Early 1800s - The first human cases of
cutaneous anthrax in the US and UK were reported in men who contracted the disease after having been in contact with infected livestock.
The disease was also called Wool Sorter’s disease and Rag Picker’s disease .
1876 - German bacteriologist Robert Koch confirmed bacterial origin of anthrax.
1881: Louis Pasteur developed the first vaccine
Anthrax a biological weapon
1915 - German agents injected horses, mules, and cattle with anthrax during WWI. This was the first recorded use of anthrax as a biological weapon.
1979 - In Soviet Union, aerosolized anthrax spores were released accidentally at a military facility, affecting 94 and killing 64 people.
1995 - Iraq produced 8,500 liters of concentrated anthrax as part of the biological weapon program under Saddam Hussein’s administration.
Anthrax cases 2001
22 cases
-11 cutaneous
-11 inhalational 5 deaths ( all inhalational )
-case in Florida
-2 postal workers in Maryland -hospital worker in NY city Farm woman in Connecticut
Bacillus anthracis
Gram positive rod has a diameter of 1-1.5 µm and a length of 3-10 µm. Facilitative anaerobe Belogns to the B.cereus family
- Nonmotile
-glutamyl-polypeptide capsule
-soil dwelling
Bacillus anthracis
1200 strains distributed worldwide Forms spores
-infectious form
-1micrometer in size Vegetative state
-non infectious
- fragile
The spore
Sporulation conditions:
-starvation
- presence of oxygen
-changes in environmental conditions - resistant to cold, heat,dryness and chemicals -lethal dose of 2500 to 5500 spores - spore viability increases in soil with organic
content, alkaline PH, high calcium concentration ,high moisture
-
Spore anatomy
Cr: core Cx: cortex Ct: coat Is: interspace Ex:exosporium
Thin-section electron micrograph
Spore anatomy The core:
-protects the spore from Uv radiation and stress
-forms the center part of the spore
- chromosomes form complexes with small acid soluble proteins abbreviated as SASP
-high levels of dipicolinic acid and ions The Cortex
- important in providing resistance to the spore and keeping the core dry.
Spore anatomy The coat
- multilayer protein shell that prevents the entry of large degradative molecules and microbe predators into the spore’s core
- flexible ridges that unfold, allowing the core's volume to increase when water enters the spore during germination.
The exosporium
-forms the outermost structure of the spore that interacts with the environment
-This protein shell is composed of surface proteins
The anthrax cycle
Cutaneous anthrax Infection of the skin due to direct contact with
B.anthracis contact with animal hides or hair, bone products, and
wool. Stages
-primary lesion appears as papule similar to an insect bite
-papule enlarges,small vesicles form on its surface
-the vesicles fill up with neutrophils and bacilli.
-the vesicles undergoe necrosis and form painless alcer surrounded by an eschar
tr
Cutaneus anthrax
Most common naturally occurring form Case fatality after infection
-untreated 20 %
-with antimicrobial therapy 2% Complications
infection can spread into blood stream and cause shock and death.
Treatment
doxycyclene antibiotic for 60 days
Cutaneus anthrax
Gastrointestinal anthrax Caused by the ingestion of meat
contaminating Bacillus anthracis Uncommon in the US Case fatality rate:50-75% 2 different forms of GI anthrax
1) oral- pharyngeal
2) abdominal
Gastrointestinal anthrax
Oral -pharyngeal form
results from the deposition and germination of spores in the upper GI tract
causes infection of lymph glands and lymph channels,edema,sepsis
Abdominal form
-develops from the disposition and germination of spores in the lower GI tract.
-causes gastroenteritis and symptoms such as vomiting and abdominal pain
Gastrointestinal anthrax
Abdominal anthrax
oral-Pharyngeal anthrax
Inhalation anthrax
The most lethal type of anthrax Caused by the inhalation of anthrax spores. Initial phase:
- nonspecific, flue like symptoms, fever and malaise Second phase:
-respiratory distress
-dyspnea, cyonosis ,mediastinal widening and death Case fatality :75-90% if untreated
Inhalation anthrax
Inhalation anthrax Diagnosis:
- Blood cultures
- Chest x-ray or CT scan of the chest
- Sputum cultures Treatment: Inhalation anthrax is usually treated
with intravenous (IV) ciprofloxacin plus another antibiotic sixty days
Complications: Hemorrhagic meningitis, shock and death
Pathogenesis The most studied strain of anthrax is the aimes strain Consists of one chromosome and 2 plasmids (pX01
and pX02) that carry genes that encode the virulence factors.
Px01
- protective antigen (PA) Px02:
-edema factor (EF)
-Lethal factor (LF)
-poly-D-glutamic acid capsule
Pathogenesis
Capsule: protects the bacteria in the vagitative state against phagocytosis.
PA: binds to the cell host's cell receptor and help AF And EF enter the cell by endocytosis.
EF: is an adenylate cyclase that affects all cells
1- converting ATP to cAMP
2- cAmp concentration increases
3-water imbalance occurs
4-edema
pathogenesis
LF: metalloprotease that affects only macrophages
-cleaves most activated protein kinase kinases MAPKKS and trigger an apoptotic pathway to lyses the cells
LF+PA necrosis
EF+PA edema
EF+LF inactive
EF+LF+PA
edema+ necrosis
Pathogenesis mechanism
The Fight against anthrax
vaccines and antitoxins target the protective antigen PA
Vaccines:
-first-generation:
(+) contained a culture from an attenuated strain
(-) difficult to manufacture and has side effects
-second-generation
(+) contained nontoxic recombinant rPA molecule
(-) slow and expensive
New breakthrough
Researchers at university of taxis medical branch rapid immunization of large, at-risk populations
after potential exposure to anthrax
- vaccine applied to mucosal surfaces to replace intramuscular vaccination
-There study examined the use of soybean oil-and-water nanoemulsions (NEs) as a mucosal adjuvant for an rPA vaccine to replace the aluminum adjuvant of the traditional vaccines
Results
NE immunization was effective in inducing both serum anti-PA immunoglobulin IgA and IgG antibodies
high titers of lethal-toxin-neutralizing serum antibodies
sGuinea pigs nasally immunized with rPA-NE vaccine were protected against an intradermal challenge with 1,000 times the 50% lethal dose
a needle-free anthrax vaccine requiring fewer doses and having fewer side effects than the traditional vailable human vaccine
results
Conclusion
although the rate of natural anthrax infection has declined, this topic remains a controversial one because of its relation to bio terrorism
this breakthrough is an excellent starting point and scientists should introduce the vaccine to humans and test it's success rate. In the future, research must focus on finding an antitoxin that can effectively cure vaccinated and non vaccinated humans after infection or exposure to the spores.
the fight against anthrax and all other biological weapons should be taken more seriously in the future to prevent any surprising attack from taking place.
Reference
Baillie, L. 2001. The development of new vaccines against anthrax. J. Appl. Microbiol. 9:609–613.
Bailey-Smith, K., Todd, S.J., Southworth, T.W., Proctor, J., Moir, A., 2005. The ExsA protein of Bacillus cereus is required for assembly of coat and exosporium onto the spore surface. J. Bacteriol. 187, 3800–3806.
Franz D. 2009. Preparedness for an anthrax attack. Molecular aspects of medicine 30:503-510.
Friedlander A. M. 1986. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. Journal of Biological Chemistry 261:7123.
Shadonly S., T. Smith. 2008. Anthrax. Journal of the American Veterinary Medical Association 233:63-72.
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