Week Biological 8-agents of terrorism and warfare (focus on Anthrax infection)

Bioterrorism

the malevolent use of bacteria, viruses or toxins against humans and animals in an attempt to cause harm and fear.

deal bioterrorism agent include:

• Accessibility

• Durability

• Infectiousness

Agents ranked A-C by Centre for Disease Control based on perceived threat. Anthrax and Smallpox are category A agents.

used throughout history

-black plague; catapult dead ppl body over walls

-smallpox; colonizers with indigenous people

-anthrax; used to by germans to kill ally cattle, Russian bioweapons leakage caused anthrax to kill village

Biological weapons

• -cheap and easy to make compared to nuclear and chemical weapons

• -point of release is typically unknown = “silent” (escape easy)

• -very contagious = spreads very effectively

• -causes significant and widespread panic

High-priority agent

include organisms that pose a risk to national security because they:

• can be easily disseminated or transmitted from person to person;

• result in high mortality rates and have the potential for major public health impact

• might cause public panic and social disruption

• require special action for public health preparedness.

Bacillus anthracis

-gram-positive bacterium

-forms stable endospores when nutrients are limited

the spore is the infectious particle

-long-lived

-resistant to destruction/environment -

ability to cause lethal infections

3 main clinical forms of disease caused by anthrax:

• Cutaneous anthrax (common-contact with spores or infected animals – entry through cuts in hands)

• Gastrointestinal anthrax (ingestion of spore-contaminated meat)

• Inhalational anthrax (rare-aerosolized spores are inhaled

Cutaneous anthrax

-most common

-contact with spores or infected animals – entry through cuts in hands

-ulceration of skin that clears without scarring – antibiotics recommended

Gastrointestinal anthrax

-ingestion of spore-contaminated meat

-bloody stools, massive edema and abdominal pain -

mortality is very high = shock and blood/fluid los

Inhalational anthrax

-rare -aerosolized spores are inhaled

-spores reaching the alveoli are engulfed by macrophages and transported to lymph nodes where replication occurs

-flu-like symptoms, extensive internal hemorrhage, meningitis

-very high mortality = fatal unless treated very early (wiithin 48 hours need intravenous antibiotics)

Anthrax

is on Category A of the list of Priority Biological Agents of the CDC = highest priority research

weaponization” of anthrax: drying and milling the spores to a size that reaches deep into the lungs and remains airborne longer

-anthrax does not spread from person to person

-rapid progression to death means that antibiotics and vaccine supplies critical

– top choice for germ warfare!

• Ease of manufacture and dissemination

• Dissemination could be as high tech as missiles, aerial bombs or as low tech as the mail! à 2001 in the USA

were used in 2001 mail attack; traced the letter spores back to the stocks that Ivins handled, as Anthrax spores have sub-populations bearing some mutations

Bacillus anthracis virulence

depends on the presence of its 2 large plasmids:

• Plasmid pXO2 → genes for the capsule (needed for infection to spread, and spore durability

• Plasmid pXO1 → toxins (toxins below)

  • Edema toxin –contains edema factor (EF), which is a calmodulin-dependent adenylate cyclase à increases cAMP levels à upsets cellular water balance

  • Lethal toxin –contains lethal factor (LF), a zinc metalloprotease which inactivates many cytosolic enzymes including MAPK.

  • Protective antigen (PA) – mediates cell entry of LF & EF

Anthrax treatment

• -Antibiotics = penicillin, tetracycline, erythromycin, and ciprofloxacin.

  • Inhalational anthrax requires infusion of antibiotics continuously

• Military Vaccine Agency of the US has an FDA approved effective vaccine

  • -only available to the military and “at risk” individuals (until now)

  • -still used in conjunction with antibiotics if an “attack” were to occur

  • -has been linked to “Gulf war syndrome”

    • -multi-symptom rheumatic disorder in veterans of the 1990-1991 war

    • -The August 2002 article is entitled "Antibodies to Squalene in Recipients of Anthrax Vaccine" (Exp. Mol. Pathol. 73,19-27 (2002))

Plague

• –Caused by a bacterium: Yersinia pestis - gram negative bacterium (Coccobacillus)

  • - many virulence factors that are anti-phagocytic and anti-inflammatory -also a lipopolysaccharide endotoxin

Multiple plague pandemics in history -The Black Death; in ~1346; killed 30 million in Europe!

Controlled through the use of antibiotics and rodent transmission - ~2000 cases/year worldwide (WHO, 2016) -in 2017 ~ 2000 cases in Madagascar alone!

A zoonotic infection of rodents

• rats are the animal reservoir and is transmitted between them by the bite of their fleas

• -humans become infected when fleas bite them after biting an infected rodent

Plague various pathnogenesis

Bacteria migrate to the lymph nodes

• Associate with mononuclear cells and multiply

  • cause

    • -swelling = bubo =bubonic plague

    • –fever, chills, bubos

migration to the lungs = pneumonic plague

• Can also get primary pneumonic plague by direct inhalation of bacteria

• -symptoms similar to pneumonia

disseminate to the bloodstream = septicemic plague

• -black lesions on fingers and toes = Black death

Plague as a bioterror agent

–Contagious =pneumonic form; spreads easily from human to human

–Stable -up to 1 hour in aerosolized form

–Highly infective - 100-500 organisms can cause significant infection

–High mortality =100% for pneumonic form

–Public panic –Difficult to diagnose quickly; e.g. pneumomic plague would manifest as pneumonia -if treatment is not started within 24 hours of infection, mortality =100%

(Natural disasters can release bacteria to cause plague)

Smallpox

is caused by an orthopox (DNA) virus = variola virus

last naturally occurring case was in 1977 in Somalia -WHO declared the disease eradicated in 1980 -vaccination discontinued since then -original vaccine was live vaccinia (related virus) -the world is no longer immune to the viru

–Disease is characterized by disfiguring skin eruptions, fever and a high rate of mortality

-antivirals are not all that effective

-vaccination is the best protective measure

-rapid isolation would be required of infected individuals

Viral Hemorrhagic fevers

can be contracted by a bite of a mosquito, animal excrement or contact with infected animals or human

Examples are Ebola, Marburg, Lassa, Junin and Machupo

were developed as bioweapons in Russia and US until the mid-1990s (n an aerosolized attack)

Lack of humoral response in those infected -require good antivirals = seriously lacking! (need vaccinations, but are highly mutating/emerging virus thus needs to be updated)

Botulinum toxin

Made by the spore-forming microbe, Clostridium botulinnum

C. botulinnum is ubiquitous in soil and very easy to culture -easy to purify toxin -0.7 to 0.9μg inhaled is sufficient to kill a 70Kg human!

Most potent toxin known to man!

Acts at neuromuscular junctions to prevent release of acetylcholine

-a neurotransmitter that stimulates muscle contraction

-leads to paralysis, eventually respiratory paralysis

Can be aerosolized or contaminate the food supply

-BoTox only contains about 0.3% of the lethal inhalational dose!