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A Historical Look at Bioterrorism
Christine Chung
Aaron Little
Angela Serrano
Laurie Wallis
Introduction
• Bioterrorism is a growing concern in social, political, and
scientific communities globally
• Historically, Category A Select Agents, as identified by
the CDC, have been used or acquired with intent to
disseminate
• Category A Select Agents are those with high morbidity
or mortality combined with high transmission rates
including Anthrax, Botulism, Plague, Smallpox. Also
included is Category B Agent, Salmonella because of the
relative ease of acquisition and historical use.
• Note: Follow hyperlinked buttons in the timeline to view
Select Agent information.
Biological Weapons Timeline
• 1346: Plague victims are catapulted over city walls
during the Tarter siege of Kaffa.
• 1746: British army distributes smallpox infected blankets
to Native Americans during the “French and Indian War”
• 1925: The Geneva Protocol is signed, banning the use
of BW in warfare
• 1932 – 1945: Japan uses BW against China and POWs
• 1942: British test weaponized anthrax on sheep on
Gruinard Island, Scotland leaving the island under
quarantine for 48 years.
Biological Weapons Timeline
• 1969: US President Richard Nixon announces that the
US will never use BW under any circumstances
• 1972: The Biological Weapons Convention is signed.
There are currently 163 signatories to the BWC.
• 1975: US signs the Geneva Protocol
• 1979: Anthrax is accidentally released from BW
production facility in Sverdlovsk, USSR.
• 1984: The Rajneeshees deliberately contaminate salad
bars in Oregon with salmonella bacteria.
• 1992: Russian President Boris Yeltsin reaffirms Russia’s
commitment to the BWC after disclosing the existence of
Biopreparat, a major clandestine BW program
Biological Weapons Timeline
• 1995: Larry Wayne Harris obtains vials of plague from
ATCC.
• 1995: Aum Shinrikyo develops and attempts to
disseminated botulinum toxin and anthrax.
• 1998: All US Armed Service personnel must be
vaccinated against anthrax.
• 2001: Genetic manipulation significantly increases
virulence of mousepox virus (similar to smallpox)
• 2001: Letters containing weaponized anthrax are sent
through the US postal system.
• 2002: Polio virus is artificially synthesized within
laboratory
• 2009 and beyond: Advances in biotechnology create
countless benefits, but introduce new proliferation
threats…
Bacillus anthracis Toxin
• Disease Caused:
− Anthrax
• Produced by Bacillus anthracis
− Related to B. Cereus and B. thuringiensis
which do not produce capsules and not infectious to humans
• Large gram-positive rod
• Capable of endosporulation, particularly in high CO2
(>5%) concentration
− Spores can survive in soil and harsh conditions for decades
• Zoonotic disease primarily infects cattle, horses, goats,
sheep
− Natural transmission is extremely rare
− No human to human transmission
Bacillus anthracis Toxin
• 89 known strains, including
– Ames strain of 2001 attacks
– Vollum strain of 1935 WWII Gruinard
bioweapon trials
– Sterne strain for vaccines
• Pathogenicity is via poly-D-glutamyl
capsule and 3 factors
– Edema Factor (EF)
– Protective Antigen (PA)
– Lethal Factor (LF)
• LD50: varies greatly within species
– Rat: 1,590 colony-forming units/kg
– Monkey 7.5 million units/kg
– Human estimated 8,000 units/kg
Anthrax
• Pathogenic B. anthracis requires a capsule to mediate
the invasive stage and a multicomponent toxin to
mediate the toxigenic stage
– poly-D-glutamate polypeptite coating nontoxic, protects against
complement, and phagocytosis and bactericidal components
of macrophages
– construction requires pX02 plasmid, obtained from conjugation
– Protective Antigen (PA) acts as the binding (B) domain
– Edema Factor (EF) acts as an active (A) domain, homologous
to the alpha domain of adenylate cyclase
– Lethal Factor (LF) acts as an active (A) domain, a Zn++
dependent protease and member of the MAPKK family
Anthrax
• Mechanism
– PA, EF, and LF combine to form an A-B enzymatic binding
structure
– cause edema, attracting leucocytes to the area
– impair macrophage and neutrophil phagocytosis
• PA+EF elevates cAMP levels, reducing permeability
• also depletes ATP, required for engulfment process
– PA+LF act to disrupt cell signaling pathway; not entirely
understood
– septicemia causes death from oxygen depletion, secondary
shock, increased vascular permeability, respiratory failure,
cardiac failure; sudden and unexpected after 3-10 days
Anthrax
• Routes of infection
– Cutaneous: boil, then eschar, then necrotic ulcer; painless; minor
lethality
– Gastrointestinal: severe gastrointestinal irritability; highly lethal route
– Pulmonary: induces flu-like symptoms; most lethal route
• Treatment
– Vaccination for potential contact, given yearly and at least 4 weeks prior
to exposure
– Antibiotics (eg penicillin) for inhalation victims, given within 24 hours
– Cutaneous inoculation has minor lethality, usually none with antibiotics
• Cleanup
– Spores are hardy, resistant to dessication, heat, extreme chemicals,
and natural decay
– CDC and BW protocol recommend steam sterilization or burning for at
least 30 minutes
– other approved chemicals may not destroy them all
Anthrax in Bioterrorism
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Location: More than 60 sites in the US
Perpetrator: Bruce Ivins, suspect
Objective: Unknown
Organism:
– Bacillus anthracis spores
• Dissemination
“Amerithrax”
– 4-7 letters sent through postal system
– 22 confirmed cases of anthrax
• 11 Cutaneous
• 11 Inhalational (5 Deaths)
• Outcome: FBI Named Bruce Ivins of
USAMRIID as suspect. Ivins committed
suicide before he could be tried.
Back to Timeline
Plague
• Organism:
– Yersinia pestis (formerly known as
Pasteurella pestis)
• Location: Africa, former Soviet Union,
the Americas, Asia, and the Middle East
• Types of Plague:
– Sylvatic plague: in wild rodent populations
– Urban plague: involves rats and is the major source for human
endemics
• The WHO (World Health Organization) reports 1,000-3,000 cases of
plague worldwide each year, with an average of 5-15 in the western
U.S. – probably an underestimate
– Highest incidence in Africa (>90% of cases worldwide)
– 90% of U.S. cases in New Mexico, Arizona, Colorado, and California
Urban Plague
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Bubonic Plague
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Pneumonic Plague
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Infection of lymphatic system
Occurs within a week of infected flea bite
Known as “Black Death” as multiplication of bacteria produces “buboes” (swollen, painful
lymph nodes)
75% mortality rate
Up to 15% of bubonic plague victims develop secondary pneumonic plague
Infection of respiratory system
Occurs in crowded conditions when contaminated respiratory droplets are expelled by
infected humans and directly inhaled by others
Characterized by shorter incubation period and greater mortality (90%)
Septicemic Plague
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“blood-poisoning” form
Can result from bubonic and pneumonic plague when bacteria enters the bloodstream from
the lymphatic and respiratory systems
Least common form of plague, characterized by high fevers, purple skin patches and
vomiting
Can cause DIC (disseminated intravascular coagulation)
Almost always fatal (near 100%)
Yersinia pestis
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Gram-negative coccobacillus (an Enterobacteriaceae), non-motile
Facultative anaerobe
“Safety pin” appearance in bipolar staining
Colonial Morphology: grey-white, “fried-egg”, irregularity, hemolytic, grows
faster and larger at 28°C
Produces a thick anti-phagocytic slime layer
Produces two antiphagocytic components necessary for virulence:
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F1 antigen and VW antigens
Both produced at 37°, not lower, thus not virulent in fleas that have body temp. of 25°)
Expresses vadBC gene, allowing for adherence and invasion of epithelium
Type III secretion system: allows bacteria to inject six different substances
into macrophages and immune cells for cytolysis, apoptosis, platelet
aggregation, actin microfilament disruption (limits phagocytosis by targeting
actin)
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Necessary for virulence
Yersinia pestis (cont.)
• Bacteria can survive for weeks outside of a host
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Viable in blood for 100 days
Dried blood for three weeks
In flea feces for five weeks
In infected human bodies for up to
270 days
– Can survive in soil for some time
• Fleas act as vectors
• Mainly rodents are the reservoirs, but hundreds of
animals can be potential hosts, including cats, dogs,
rabbits, and squirrels (most prevalent vector in the U.S.)
Mechanisms of Action
• (Pneumonic plague) Can spread between humans through sneezing,
coughing, and/or direct contact of infected tissue
– Estimated that only 50kg of Y. pestis released as an aersol in a city of 5
million would infect 150,000, of which 36,000 would die
• Most carnivores, except cats, are resistant to plague infection
• Epidemiology
– Occurs in urban and/or wild rodent populations
– Humans acquire primarily via infected fleas
– Y. pestis multiplies in flea intestinal tract
• Known mechanisms
– Sites of Entry and Exit
– Incubation period: 1-3 days (pneumonic); 2-6 days (bubonic)
– Infection spreads from lymph nodes near the bite site where swelling
occurs, then spreads to other organs such as the spleen, liver, lungs,
skin, mucous membranes, and the brain (but usually not the kidney)
Current Research
on Mechanisms, etc.
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The CDC considers an average of one flea per rodent as the maximum
threshold to reduce the risk of Y. pestis transmission to humans.
– A reduction of rodent and/or flea populations is optimal
– Chitin synthesis inhibitors used to reduce flea populations effectively on certain
species of rodents
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Type III secretion of Y. pestis targeted for new therapeutics
Interleukin-10-deficient mice are resistant to Y. pestis
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Heterozygotes also able to survive high doses of IV infections
Two substrains of 129 mice resistant to high-dose KIM5
Resistance is not recessive
129-derived genomic DNA near IL-10 confers resistant to Y. pestis KIM5
Ail (Attachment and Invasion locus) protein found to be crucial in binding
and cytotoxic Yop protein delivery into the host cell (type III secretion)
– Single deletion in ail locus severely hindered Yop delivery
– Mice with KIM5 ∆ail mutant:
• >3,000-fold increased LD50
• 1,000-fold less bacteria in spleens, livers, and lungs
Effects
• Symptoms
– General malaise; pain or tenderness at regional lymph nodes;
septicemia; DIC; convulsions; shock; headache; prostration; bacteria in
blood
• “Signs”
– High fever (hyperpyrexia); diffuse, hemorraghic changes in the skin;
dark skin at extremities that led to the name “black death”; coughing and
sneezing in the case of pneumonic plague
• Secondary Illnesses
– Complications: DIC, pneumonia, meningitis
– Bubonic plague victims may develop pneumonic plague, which is
contagious through coughing and considered the most severe form of
the disease
Plague in Bioterrorism
• Location: Ningbo, China and Changde, China
• Perpetrator: Japanese secret biological
warfare research facility (Unit 731)
• Objective: Infect civilian populations
• Organism:
– Yersinia pestis
• Dissemination
– Ceramic bombs full of bubonic plague-carrying fleas
dropped over Ningbo by the Imperial Japanese Army Air
Force
– 80% of fleas survived the bombing to infect civilians
– Changde: plague-contaminated foods were distributed to
civilians and water supplies contaminated
• Outcome: Largely ineffective in comparison to
distribution as aerosols; caused epidemic plague
outbreaks; 400,000 Chinese killed in Ningbo
Back to Timeline
Plague Events
(as Biological weapon)
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Earliest reference to bubonic plague (approx. 1320 BC) in book of I Samuel
6th Century: Plague of Justinian (First Pandemic) through Byzantine Empire, greatly weakening
the Roman empire by reducing the population by one-third
1346: Mongol warriors of the Golden Horde threw infected corpses over the walls of the besieged
Crimean city of Kaffa (in present day Ukraine)
1347-1351: “Black Death” (Second Pandemic), possibly originated in Gobi Desert
1710: Russian forces attacked the Swedes by fling plague-infected corpses over the city walls of
Reval in Estonia (Tallinn)
1855-1950s: The Third Pandemic, originated in China, spread worldwide via ships
WWI: the German Army allegedly spread plague in St. Petersburg, Russia
1940: Imperial Japanese Army Air Force bomb Ningbo with plague-carrying flea ceramic bombs
1941: Unit 731 air-drop plague-carrying fleas on Changde
1944: the Japanese planned on dropping porcelain plague-flea bombs on invading Gis to defend
their airstrip on Saipan, but failed when carrier submarine sank before reaching the island
Biological warfare generally not used after WWII, but challenged by China and North Korea, who
accuse the U.S. of using disease-carrying insects against them during the Korean War.
1953: U.S. initiated disease vector weaponization efforts with focus on plague-fleas, etc.
Vietnam War: plague was endemic among natives; U.S. soldiers well-protected with vaccines
1995: Discovery of multi-drug resistant (MDR) strain of plague in Madagascar
1996: an Ohio man attempted to obtain bubonic plague cultures through the mail
Pathogenesis
• Y. pestis primarily a rodent pathogen; humans are accidental hosts
when bitten by infected rat fleas
• Y. pestis grows and multiplies in flea’s intestinal tract, blocking the
flea’s proventriculus, and loses its capsular layer. Several proteins
including hemin storage (Hms) system and Yersinia murine toxin
(Ymt) contribute to maintenance of bacteria in flea’s digestive tract.
• Hms genetic loci aggregate in esophagus and proventriculus of flea,
which ruptures blood cells, which inhibits feeding causing the flea to
feel hungry.
• Ingested blood is pumped into the esophagus, dislodging the
bacteria cultivating there and is regurgitated and transferred into a
new host (i.e. humans) when fleas feed
• Most get phagocytosed and killed by leukocytes in human.
Pathogenesis (cont.)
• Few are taken up by tissue macrophages, which are unable to kill
the bacteria and instead provide a protected environment.
• Y. pestis kills the macrophage in order to enter the extracellular
environment, resisting phagocytosis by the polymorphs.
• Quickly spread to the draining lymph nodes, which are inflamed,
giving rise to black buboes.
• Within hours of the flea bite, the infection enters the bloodstream,
reaching the liver, spleen, and lungs.
• Human host develops severe bacterial pneumonia, releasing large
numbers of Y. pestis into the air with coughing fits.
Present uses and/or
Possible future uses
• Present treatments/therapy
– Rapid diagnosis essential
• Rapid disease progression
• High mortality rate
– Bubonic plague: 75% mortality in few days
– Pneumonic plague: >90% mortality within 24 hours
– Without treatment, fatality rates increase up to 90% for bubonic plague,
100% for septicemic or pneumonic plague
– With treatment, fatality rate = 5-20%
• Rapid treatment crucial to survival rates
– Antibiotics: Streptomycin, chloramphenicol, tetracycline,
fluoroquinolones, sulfonamides, ciprofloxacin, and potentially
doxycycline or gentamicin, etc.
– Multi-drug resistant strains have been isolated
– Best laboratory diagnosis is made by PCR, etc.
Present uses and/or
Possible future uses
• Weaponized plague development and Other Current Events
– On the list of potential terrorist agents
– Transmission by aerosols is potentially deadly and can spread from
person to person
– Institute of Ultra Pure Biochemical Preparations, Leningrad: a
weaponized plague center
– Al Qaeda
• Roughly 40 al-Qaeda terrorists reportedly died from bubonic plague in their
Algerian training camp
• Late 1990s: Osama bin Laden set up 19 chemical and biological weapons
laboratories in Afghanistan, which were stocked with anthrax, plague, and
botulinum toxins.
• Possible threats: could spread in public by a lone suicidal bioterrorist (i.e. in
subways), or could contaminate self with the plague first to conduct a
bioterrorist attack
– Could take up to a week for symptoms to appear
– 2002: two NYC residents acquired plague from New Mexico
Present uses and/or
Possible future uses
• Present research being conducted in the maintenance of plague
– Experiments with genetic engineering of vaccines based on F1 and V
antigens are underway
• Bacteria lacking F1 antigen are still virulent
• These vaccines may not fully protect potential hosts
– Research suggests that descendants of medieval European plague
survivors are less likely to catch plague
– Recent research indicates that ongoing outbreaks of plague can be
caused by viral hemorrhagic disease, similar to Ebola
– A handful of Western laboratories are actively conducting research on
MDR Y. pestis (resistant to at least eight drugs traditionally used to treat
plague)
• Should conduct additional research to effectively fight MDR strain
Present uses and/or
Possible future uses
• Prevention and vaccination
– By law, pneumonic plague patients must be isolated
– Sanitation measures
• Control of rat populations and elimination of fleas; etc.
– Formalin-inactivated vaccine for adults (age 18-61) at high risk, and
continuous booster shots
• Not very effective
• May lead to severe inflammation
– As of the mid-1990s, the vaccine is no longer available in the U.S.
– Research being conducted currently for more effective vaccines
– Scientists hypothesize that a mutation in the CCR5 gene, which gives
rise to a natural immunity to the HIV virus, may also confer immunity to
Y. pestis
– Currently, hospitals are poorly equipped/prepared to deal with patients
in the case bioterrorism may occur.
Back to Timeline
Salmonella
• Disease Caused:
− Salmonellosis/Gastroenteritis/Enteric Fevers
(including Typhoid Fever)
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Gram-negative Bacterium
Characterized by O, H, and Vi antigens
Ingested in contaminated food and water
Zoonotic-worldwide human and animal
disease
• Resilient and capable of survival for several
years
• Sensitive to moist and dry heat and many
disinfectants
Salmonella
• Mechanism
– Bacteria pass through gastric acid barrier and invades
mucosa of small and large intestines and produce toxins
– Irritation of the small and large intestines
• Results of Exposure
– Profuse vomiting and diarrhea
– Leads to dehydration
– Can result in death with severe dehydration.
• Treatment
– Antibiotics
– Hydration
Salmonella in Bioterrorism
• Location: The Dalles, Oregon
• Perpetrator: Rajneesh Cult
• Objective: Gain control of the Wasco County
Court by affecting the election
• Organism: Salmonella typhimurium
Bhagwan
Shree
Rajneesh
– Purchased from commercial supplier
• Dissemination
– Restaurant salad bars
– 751 illnesses
• Early investigation by CDC suggested the event
was a naturally occurring outbreak
• Cult member arrested on unrelated charge
confessed involvement with the event
Back to Timeline
Smallpox
• Disease caused by Variola major virus.
• Humans are the only natural reservoir for variola virus
− Originated in Egypt or India over 3000 years ago
− Eradicated in nature by vaccination programs in 1970-1980s.
• Only known stocks of virus at CDC in Atlanta, and a
Russian repository.
• Mortality rate of 30%
− Up to 90% mortality for flat and hemorrhagic forms of virus.
Smallpox
• Mechanism
− Entry through the respiratory mucosa
− virus migrates rapidly to regional lymph nodes, then to
spleen, bone marrow, kidneys, and liver
− virus localizes in small blood vessels of the dermis and
oropharyngeal mucosa, and evolves into skin lesions.
• Results of Exposure
− Incubation period 7-14 days
− Flu-like symptoms
− Development of pustules
• Treatment
− None
Smallpox in Bioterrorism
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Location: North America during French and Indian War
Perpetrator: British Forces in North America
Objective: Infect Native Americans with Smallpox disease
Organism
− Variola Major
• Dissemination:
− Blankets used by smallpox patients given to
Native Americans as “gifts” during war
− 50% Native American mortality rate
• Outcome: Smallpox outbreak claimed lives of many Native
Americans, British leader Jeffrey Amherst claimed parts of
Canada and the United States in war victory
Back to Timeline
Botulinum Toxin
• Disease caused: Botulism
• Produced by Clostridium botulinum, C. baratii, and
C. butyricum
– Multiple types of toxin: A, B, C, D, E, F, G
– Only A, B, E, and F produce human disease
• Spore forming bacteria is highly stable
• Toxic protein is degraded by heat and
humidity – relatively stable for a protein
• LD50: 0.001µg/kg
– The lowest known LD50 of all toxins
• Found in soil, water, and contaminated food
• Therapeutic use as a paralyzing agent when
highly diluted
Botulinum Toxin
• Mechanism
– Neurotoxin degrades the SNARE complex in the synaptic
bulb.
– Permanently interferes with the release of acetylcholine,
preventing nerve stimulation for muscle contraction.
• Results of Exposure
– Paralysis
– Respiratory failure
• Treatment
– Antitoxin (limited supplies)
– Supportive care
• Ventilator machine
• Extensive rehab
Botulinum Toxin in Bioterrorism
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Location: Tokyo, Japan
Perpetrator: Aum Shinrikyo Cult
Objective: Over throw government via targeted
assassination and pubic dissemination.
Organisms:
– Bacillus anthracis
• Vaccine strain
– Clostridium botulinum
• Environmental isolate
• Avirulent strain
– Ebola virus
Aerosolization of Bacillus
anthracis and botulinum toxin by
Aum Shinrikyo
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• Attempted to acquire from Zaire outbreak under guise of
an “Humanitarian mission”
Dissemination
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Aerosolization in Tokyo
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B. anthracis
Botulinum toxin
Outcome:
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Use of non-virulent strains and ineffective dissemination
methods resulted in no casualties from biological weapons
Successful sarin nerve gas attack in subway
Leader Asahara was convicted of criminal activity
Back to Timeline
Summary
• The future threat of bioterrorism is increasing with the
advances in biotechnology.
– Increasing ease of acquisition and production
• Sequencing technology advances and publications
• Small-scale operations sufficient to incite fear
– Historical failures decreasing
• many past attempts failed because of bad science
• Terrorists gaining required knowledge and skills
– Political treaties / federal restrictions reducing ability of research
– Biodefense difficulties
• Vaccines are expensive, and preventative only
• antibiotics are best line of defense, but select agents increasingly resistant
• Slow spreading awareness of complex topics
Back to Timeline
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