Transcript Toxin: Atracotoxin aka (spider toxin)

A Study on the Toxin: Atracotoxin
AKA (spider toxin)
Australian Funnel Web Spider
Presented by:
Anu Bhalla, Patrick Manzanares, &
Reshawn Jackson
Why Examine?
• The Australian Funnel-Web Spider releases the
atracotoxin on non-dry bite victims (venom secreted). As
spiders, they are among the third most venomous in the
world. By studying them we are able to understand how
to properly behave/react around them, and what to
expect if bitten by them.
Species producing Atracotoxin
• Hadronyche
• Atrax Robustus
Hadronyche vs. Atrax Robustus
• Similarities Between Two Species
– Body lengths ranging from 1 cm to 5 cm
– Located in Australia: Eastern Seaboard
– Both can be lethal to humans
– Fatalities occur from 15 minutes- 6 days
– Males have significantly shorter life spans then females
– Male toxin is 5x stronger than female toxin
– Toxins from both species are almost similar in structure and
mechanisms.
• Differences Between Two Species
– Hadronyche are slightly more lethal then Atrax Robustus
– Atrax Robustus venom causes sustained hypotension, which is not
seen in Hadronyche.
Toxin Characteristics
• % Dry Bites
– 10%-25% produce toxicity
• Lethal Dose in Observed Species:
– Monkey: 0.2mg/kg
– Mice: 1.5ug/kg
Human Fatalities
• (55-58) know deaths
• 30-40 cases per year seeking treatment
• Lethal in man/primates/mice but not lethal in some
other lab animals unless given extremely high
doses (literature does not specify genus types, or
threshold that high dosage must reach).
Toxin Characteristics
• Biochemistry & Mechanism
– Active component: Robustoxin
– Contains high levels of hyaluronidase
(responsible for toxin spreading through
tissues).
• Hyaluronidase lowers the viscosity of
hyaluronic acid, thereby increasing tissue
permeability, which allows toxin to spread
into inner layer of stated tissue.
• Once inside, toxin has greater potential to
cause damage.
Toxin Characteristics
Biochemistry & Mechanism (Cont)
• Slows inactivation of voltage gated
Na+ channels.
• Creates surplus of Na+ ions in cell
• Inhibition and spontaneous transmitter
release
• Results in a continued firing of action
potentials
• Such behavior causes the muscles or
other tissue to become ‘over-excited.’
Biochemistry and Mechanisms (Cont)
– As a result of excessive Na intake, both the Presynaptic neurotransmitter of
autonomic and motor neurons are targeted for disruption.
– Causes inhibition of the release of transmitters (Ach, noradrenalin) as well as
increase in spontaneous transmitter release.
• Muscle Stiffness and/or epileptic seizures may result due to spontaneous
release.
• Similar action on the neuromuscular junction has been postulated.
Below Image: Voltage Sensitive Na Channel
Symptoms of Toxins
Eyes, ears, nose, and throat
• Drooping eyelids
• Double vision
• Swallowing difficulty
• Tongue spasms
Heart and blood
• Collapse
• High blood pressure
• Rapid heart rate
Lungs
• Difficulty breathing
• Pulmonary Oedema
Muscles and joints
• Joint pain
• Severe muscle spasms -- usually
in the legs and belly area
Nervous system
• Chills
• Coma
• Headache
• Numbness of mouth and lips
Skin
• Redness around the site of bite
• Sweating -- excessive
• Piloerection
Stomach and intestines
• Diarrhea
• Nausea
• Vomiting
Symptoms (cont)
• Cardiovascular- initial fall in blood pressure, then rise to
hypertensive levels.
• Acid-base disturbances- acute metabolic acidosis and respiratory
acidosis.
• Intracranial hypertension
• Temperature- hyperthermia
Factors Affecting Toxicity and Symptoms of Spider Bite
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Quantity of venom
Number of times bitten
Species of spider
Sex- M/F
Maturity- age of spider
Attack position
Bacterial flora on fangs, mouth
parts, and adjacent structures.
– Causing other infections
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Length of time for each bite
– Allowing more/less concentration
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Season:
– Venom concentration change
with seasons.
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Age of victim
– Younger/older victims are more
susceptible
Size of victim
Location of bite on victim
Pre existing health conditions
Allergic rxns
Treatments
• Pressure immobilization bandage:
– Slows venom movement & can inactivate venom
• Steroid and diuretic treatments:
Get toxin out of system faster.
• Antivenom Treatment:
– Antivenom is prepared by hyperimmunising rabbits with male A
robustus venom and is therefore a rabbit immunoglobin.
– Serum can then be injected into infected person.
– The average quantity per ampule is 100mg of purified rabbit IgG,
which is enough to neutralize in vitro four adult male spider bites.
Does the biochemistry of spiders toxin change if
spider is attacking its prey vs. defending its life?
• Toxin biochemistry does vary from attack mode to defensive mode
(Difference between exact peptide composition unknown).
• Reasons for the change in biochemistry
• Limits the cost of toxin produced.
• Energy can be spent on survival and reproduction
• Insect-selective neurotoxins (discussed further in slide 16)
– Spiders seen to release neurotoxin on insect (prey).
– Cause of secreting neurotoxin opposed to cytotoxin: Some
insects have been shown to develop resistance to toxin (insects
not specified).
– Acts as possible reflection of co-evolution between predator
(spider) and prey (insect).
Possible reasons for Divergence of Toxin
• Divergence: Notion that two toxins once had a common ancestor but
separated at some point in the past.
• Literature shows some evidence that the toxin did evolve from a
single species (the common ancestor) into 2 separate species.
• Toxins from both species are almost similar in structure and
mechanisms.
– Atrax Robustus venom, the difference being the sustained
hypotension which is not seen in Hadronyche.
• Spider had to evolve prey’s resistance to toxin.
• Possible signs of “Red Queen Hypothesis.”
• Through differential survival and reproduction, prey become resistant to
toxin.
• Similarly, through differential survival and reproduction, the properties of
the predator’s toxin becomes resistant to prey’s immunity.
• Co-evolution of predator (spider) and prey (insect) may have resulted in
a possible cytotoxin evolving to the observed neurotoxin.
Applications for Toxin
Pesticides
• Specific for insects such as cockroaches, crickets, fruit-flies and the
Helicoverpa armigera moth which destroys cotton crops. Targeting
specific species prevents the accidental killing of other insects.
• This selectivity also means that the pesticide is harmless to other
organisms so there would be no danger if it entered the food
chain. The compounds in venom are environmentally friendly and
the development of resistance to a spider venom pesticide would be
slow.
• Traditional chemical pesticides do not tend to be species specific,
are toxic to humans in large amounts and insects develop resistance
towards them relatively fast so it is easy to see why pesticides
based on spider venom are attractive.
Application for Toxin (cont)
Prevention of Brain Damage
• Oxygen deprivation caused stroke or excessive smoke inhalation
can result in nerve cell damage in the brain. Glutamate is a
neurotransmitter in the human brain and large amounts of it are
released by these damaged neurons causing the death of
neighboring nerve cells.
• The funnel-web spider produces a venom containing the active
ingredient HF-7 which blocks receptors on the nerve cell
membranes and prevents glutamate production. A drug developed
using this compound could therefore limit brain damage for stroke
victims.
References
• Isbister, Geoffrey; Graudins, Andis; White, Julian;
Warrell, David. Journal of Toxicology -- Clinical
Toxicology, Apr2003, Vol. 41 Issue 3, p291, 10p; (AN
9764026)
• Arachnid toxinology in Australia: From clinical toxicology
to potential applications.Authors:
[email protected] .Toxicon; Dec2006, Vol.
48 Issue 7, p872-898, 27p
• Handbook of clinical toxicology of animal venoms and
poisons, By Jürg Meier, Julian White
• Textbook of Biochemistry with Clinical Correlations, By
Thomas Devlin, 3rd Ed, p 329.