A Historical Look at Bioterrorism

1
A Historical Look at Bioterrorism

• Christine Chung
• Aaron Little
• Angela Serrano
• Laurie Wallis

2
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.

3
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.

4
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
  Russias commitment to the BWC after disclosing
  the existence of Biopreparat, a major clandestine
  BW program

5
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

6
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 (gt5) 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

7
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

8
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

9
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
• PAEF elevates cAMP levels, reducing permeability
• also depletes ATP, required for engulfment
  process
• PALF 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

10
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

11
Anthrax in Bioterrorism

• Location More than 60 sites in the US
• Perpetrator Bruce Ivins, suspect
• Objective Unknown
• Organism
• Bacillus anthracis spores
• Dissemination
• 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.

Amerithrax
Back to Timeline
12
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 (gt90 of cases
  worldwide)
• 90 of U.S. cases in New Mexico, Arizona,
  Colorado, and California

13
Urban Plague

• Bubonic Plague
• 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
• 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
• 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)

14
Yersinia pestis

• 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 28C
• Produces a thick anti-phagocytic slime layer
• Produces two antiphagocytic components necessary
  for virulence
• 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)
• Necessary for virulence

15
Yersinia pestis (cont.)

• Bacteria can survive for weeks outside of a host
• 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.)

16
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)

17
Current Researchon Mechanisms, etc.

• 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
• Type III secretion of Y. pestis targeted for new
  therapeutics
• Interleukin-10-deficient mice are resistant to Y.
  pestis
• 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
• gt3,000-fold increased LD50
• 1,000-fold less bacteria in spleens, livers, and
  lungs

18
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

19
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
20
Plague Events(as Biological weapon)

• 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

21
Epidemiology
22
Pathogenesis

• Y. pestis primarily a rodent pathogen humans are
  accidental hosts when bitten by infected rat
  fleas
• Y. pestis grows and multiplies in fleas
  intestinal tract, blocking the fleas
  proventriculus, and loses its capsular layer.
  Several proteins including hemin storage (Hms)
  system and Yersinia murine toxin (Ymt) contribute
  to maintenance of bacteria in fleas 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.

23
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.

24
Present uses and/orPossible future uses

• Present treatments/therapy
• Rapid diagnosis essential
• Rapid disease progression
• High mortality rate
• Bubonic plague 75 mortality in few days
• Pneumonic plague gt90 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.

25
Present uses and/orPossible 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

26
Present uses and/orPossible 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

27
Present uses and/orPossible 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
28
Salmonella

• Disease Caused
• Salmonellosis/Gastroenteritis/Enteric Fevers
  (including Typhoid Fever)
• 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

29
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

30
Salmonella in Bioterrorism
Bhagwan Shree Rajneesh

• Location The Dalles, Oregon
• Perpetrator Rajneesh Cult
• Objective Gain control of the Wasco County Court
  by affecting the election
• Organism Salmonella typhimurium
• 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
31
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.

32
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

33
Smallpox in Bioterrorism

• 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
34
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

35
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

36
Botulinum Toxin in Bioterrorism

• 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
• Attempted to acquire from Zaire outbreak under
  guise of an Humanitarian mission
• Dissemination
• Aerosolization in Tokyo
• B. anthracis
• Botulinum toxin
• Outcome
• 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

Aerosolization of Bacillus anthracis and
botulinum toxin by Aum Shinrikyo
Back to Timeline
37
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
38
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