Biology of Toxin Spring 2007 Thu Pham Nghi Tran Hong Nguyen

Basic Background Tetanus is an acute, often fatal, disease. Tetanus is an acute, often fatal, disease. Described by Hippocrates in 5 BCE. Described by Hippocrates in 5 BCE. In 1884, Carle and Rattone successfully introduced tetanus in animals. In 1884, Carle and Rattone successfully introduced tetanus in animals. Tetanus toxoid was widely used in World War II for prevention of tetanus. Tetanus toxoid was widely used in World War II for prevention of tetanus.

Four types of tetanus Local tetanus: uncommon, in which patients have persistent contraction of muscles Local tetanus: uncommon, in which patients have persistent contraction of muscles Cephalic tetanus: rare, associating with ear infections Cephalic tetanus: rare, associating with ear infections Generalized tetanus: common (80%), the disease usually presents with a descending pattern. Generalized tetanus: common (80%), the disease usually presents with a descending pattern. Neonatal tetanus: similar to generalized tetanus excepts that it affects a baby less than one month. Neonatal tetanus: similar to generalized tetanus excepts that it affects a baby less than one month.

The Bacteria Clostridium tetani produces 2 exotoxins: Clostridium tetani produces 2 exotoxins: Tetanolysin-unknown Tetanolysin-unknown Tetanospasmin- known to cause Tetanus Tetanospasmin- known to cause Tetanus C. tetani is a Gram-positive, anaerobic, rod-shaped bacterium that may be developed into terminal spore. C. tetani is a Gram-positive, anaerobic, rod-shaped bacterium that may be developed into terminal spore. C. tetani is sensitive to heat, while its spore is extremely resistant to heat, to usual antiseptics, even to some degrees of autoclave process. C. tetani is sensitive to heat, while its spore is extremely resistant to heat, to usual antiseptics, even to some degrees of autoclave process.

Sites and Source of Infection C. tetani spores are widely distributed in soil, in the intestines and feces of horses, sheep, cattle, dogs, cats, and etc. C. tetani spores are widely distributed in soil, in the intestines and feces of horses, sheep, cattle, dogs, cats, and etc. Humans usually acquire the bacteria through deep puncture wounds – great anaerobic environment for the bacteria. Humans usually acquire the bacteria through deep puncture wounds – great anaerobic environment for the bacteria. Infants – neonatal form – born without protective passive immunity and/or infection of unhealed umbilical stump. Infants – neonatal form – born without protective passive immunity and/or infection of unhealed umbilical stump.

Source distribution of Tetanus

Infection Pathway Image.google.com

Mechanism Tetanus neurotoxin (TeNT) works as an A-B type toxin. Tetanus neurotoxin (TeNT) works as an A-B type toxin. TeNT binds irreversibly to presynaptic membrane at the interneuronal junction in the spinal cord. TeNT binds irreversibly to presynaptic membrane at the interneuronal junction in the spinal cord. It blocks inhibitory neurotransmitter from releasing by the use of A or active portion of the toxin. It blocks inhibitory neurotransmitter from releasing by the use of A or active portion of the toxin.

Mechanism (cont.) Active (A) portion is a zinc dependent metalloprotease. Active (A) portion is a zinc dependent metalloprotease. (A) portion cleaves protein components, which are required for docking and fusing of synaptic vesicles. (A) portion cleaves protein components, which are required for docking and fusing of synaptic vesicles.  Inhibitory neurotransmitters cannot be released.  Prevent opposing muscle to relax when the other muscle contracts.  Opposing pairs of muscles contract at the same time.  Spastic paralysis.

Effects of C. tetani infection Spasms may cause pain in the muscles of the neck, shoulders and back. Spasms may cause pain in the muscles of the neck, shoulders and back. Tetanus affects the muscle in the jaw, a condition known as “lockjaw”. Tetanus affects the muscle in the jaw, a condition known as “lockjaw”. Affects the nerves which control body muscle activities. Affects the nerves which control body muscle activities. Affects the chest and airways, which may lead to respiratory failure. Affects the chest and airways, which may lead to respiratory failure.

Signs & Symptoms Symptoms of tetanus usually begin 8 days after infection. Symptoms of tetanus usually begin 8 days after infection. First symptoms of Tetanus infection are: First symptoms of Tetanus infection are: Headache Headache Spasms Spasms Cramping of the jaw muscles Cramping of the jaw muscles image.google.com

Signs & Symptoms Muscular irritability Muscular irritability Sensitivity to touch Sensitivity to touch High fever High fever Sore throat Sore throat Rapid heartbeat Rapid heartbeat Difficulty breathing Difficulty breathing Severe sweat Severe sweat Hypertension Hypertension image.google.com

Levels of Severity Laryngospasm Laryngospasm Fractures Fractures Nosocomial infections Nosocomial infections Bleeding inside the bowels. Bleeding inside the bowels. Severe may lead to death. Severe may lead to death. image.google.com

Tetanus surveillance (U.S.) Approximately cases reported per year in the late 1940s. Approximately cases reported per year in the late 1940s. Steadily decreased since 1947 Steadily decreased since 1947 Mortality rates declined from 30% to 10% in recent years. Mortality rates declined from 30% to 10% in recent years.

1.Reported tetanus incidence rates declined from 1980 to The decline was due to the introduction of childhood immunization and tetanus toxoid.** **The zigzag pattern shown in the graph MIGHT due to immunization taken by choice

1.Reported cases of tetanus during and were highest among people 40 years of age or older. 2.28% cases of people younger than 40 years of age during has increased to 42% from 1996 to 2000.** **The increase is related to an increased number of injection-drug users (IDU) among younger people.

Epidemiology 1.Tetanus cases reported worldwide from 1990 to It is estimated that one million cases reported worldwide. 3.Approximately 300, ,000 deaths occurred each year. Range: -Dark red= widespread -Light yellow= few cases -Gray=no case

Prevention Vaccination Vaccination Recommendation: Recommendation: One booster every ten years in adults. One booster every ten years in adults. Administer as a combined vaccine: TDap or DTaP which is against diphtheria and pertussis for children less than 7 years old. Administer as a combined vaccine: TDap or DTaP which is against diphtheria and pertussis for children less than 7 years old. The TD vaccine (tetanus and diphtheria) is commonly used in adults and children over seven. The TD vaccine (tetanus and diphtheria) is commonly used in adults and children over seven.

Treatments Clean infected wound. Clean infected wound. Surgical debridement: remove dead and infected tissues. Surgical debridement: remove dead and infected tissues. Metronidazole treatment: decrease number of infective bacteria. Metronidazole treatment: decrease number of infective bacteria. Tetanus immune globulin IV or IM. Tetanus immune globulin IV or IM. Tetanus vaccination. Tetanus vaccination.

Treatment for severe cases Tetanus immune globulin IV or IM. Tetanus immune globulin IV or IM. Magnesium infusion to prevent muscle spasm. Magnesium infusion to prevent muscle spasm. Mechanical ventilation to maintain airway. Mechanical ventilation to maintain airway. Due to an increase in muscular activity, maintaining nutrition in the body is required. Due to an increase in muscular activity, maintaining nutrition in the body is required.

Reference Clostridium tetani Office of Medical Informatics. College of Medicine. University of Florida. Retrieved on April 29, 2007 from Klein, J. and Ho, W Tetanus. Kidshealth. Retrieved on April 29, 2007 from Montecucco, C. and Schiavo, G Mechanism of action of tetanus and botulinum neurotoxins. Molecular Microbiology. Vol 13, No 1: 1-8. Tetanus CDC. Retrieved on April 29, 2007 from "Tetanus." Wikipedia Foundation. Retrieved on May 2, 2007 from