Biology of ToxinBiology of Toxin

Spring 2007Spring 2007Thu PhamThu PhamNghi TranNghi Tran

Hong NguyenHong Nguyen

Basic BackgroundBasic Background

Tetanus is an acute, often fatal, Tetanus is an acute, often fatal, disease. disease.

Described by Hippocrates in 5 BCE. Described by Hippocrates in 5 BCE. In 1884, Carle and Rattone successfully In 1884, Carle and Rattone successfully

introduced tetanus in animals.introduced tetanus in animals. Tetanus toxoid was widely used in Tetanus toxoid was widely used in

World War II for prevention of tetanus. World War II for prevention of tetanus.

Four types of tetanus Four types of tetanus Local tetanusLocal tetanus: uncommon, in which : uncommon, in which

patients have persistent contraction of patients have persistent contraction of musclesmuscles

Cephalic tetanusCephalic tetanus: rare, associating : rare, associating with ear infections with ear infections

Generalized tetanusGeneralized tetanus: common (80%), : common (80%), the disease usually presents with a the disease usually presents with a descending pattern. descending pattern.

Neonatal tetanusNeonatal tetanus: similar to : similar to generalized tetanus excepts that it generalized tetanus excepts that it affects a baby less than one month. affects a baby less than one month.

The Bacteria The Bacteria

Clostridium tetani Clostridium tetani produces 2 exotoxins:produces 2 exotoxins: Tetanolysin-unknownTetanolysin-unknown Tetanospasmin- known to cause TetanusTetanospasmin- known to cause Tetanus

C. tetaniC. tetani is a Gram-positive, anaerobic, is a Gram-positive, anaerobic, rod-shaped bacterium that may be rod-shaped bacterium that may be developed into terminal spore. developed into terminal spore.

C. tetaniC. tetani is sensitive to heat, while its is sensitive to heat, while its spore is extremely resistant to heat, to spore is extremely resistant to heat, to usual antiseptics, even to some degrees usual antiseptics, even to some degrees of autoclave process. of autoclave process.

Sites and Source of Sites and Source of InfectionInfection

C. tetaniC. tetani spores are widely distributed in spores are widely distributed in soil, in the intestines and feces of horses, soil, in the intestines and feces of horses, sheep, cattle, dogs, cats, and etc. sheep, cattle, dogs, cats, and etc.

Humans usually acquire the bacteria Humans usually acquire the bacteria through deep puncture wounds – great through deep puncture wounds – great anaerobic environment for the bacteria.anaerobic environment for the bacteria.

Infants – neonatal form – born without Infants – neonatal form – born without protective passive immunity and/or protective passive immunity and/or infection of unhealed umbilical stump.infection of unhealed umbilical stump.

Source distribution of Source distribution of Tetanus 1998-2000Tetanus 1998-2000

Infection Pathway Infection Pathway

Image.google.com

Mechanism Mechanism Tetanus neurotoxin Tetanus neurotoxin

(TeNT) works as an (TeNT) works as an A-B type toxin. A-B type toxin.

TeNT binds TeNT binds irreversibly to irreversibly to presynaptic presynaptic membrane at the membrane at the interneuronal interneuronal junction in the spinal junction in the spinal cord.cord.

It blocks inhibitory It blocks inhibitory neurotransmitter neurotransmitter from releasing by from releasing by the use of A or active the use of A or active portion of the toxin. portion of the toxin.

Mechanism (cont.)Mechanism (cont.) Active (A) portion is a zinc dependent Active (A) portion is a zinc dependent

metalloprotease. metalloprotease. (A) portion cleaves protein components, which (A) portion cleaves protein components, which

are required for docking and fusing of synaptic are required for docking and fusing of synaptic vesicles. vesicles.

Inhibitory neurotransmitters cannot be released. Inhibitory neurotransmitters cannot be released.

Prevent opposing muscle to relax when the Prevent opposing muscle to relax when the other muscle contracts. other muscle contracts.

Opposing pairs of muscles contract at the same Opposing pairs of muscles contract at the same time.time.

Spastic paralysis. Spastic paralysis.

Effects of Effects of C. tetaniC. tetani infectioninfection

Spasms may cause pain in the Spasms may cause pain in the muscles of the neck, shoulders and muscles of the neck, shoulders and back. back.

Tetanus affects the muscle in the Tetanus affects the muscle in the jaw, a condition known as “lockjaw”.jaw, a condition known as “lockjaw”.

Affects the nerves which control Affects the nerves which control body muscle activities.body muscle activities.

Affects the chest and airways, which Affects the chest and airways, which may lead to respiratory failure. may lead to respiratory failure.

Signs & Symptoms Signs & Symptoms

Symptoms of Symptoms of tetanus usually tetanus usually begin 8 days after begin 8 days after infection.infection.

First symptoms of First symptoms of Tetanus infection Tetanus infection are:are: HeadacheHeadache SpasmsSpasms Cramping of the Cramping of the

jaw musclesjaw musclesimage.google.com

Signs & SymptomsSigns & Symptoms

Muscular irritabilityMuscular irritability Sensitivity to touchSensitivity to touch High fever High fever Sore throatSore throat Rapid heartbeatRapid heartbeat Difficulty breathingDifficulty breathing Severe sweatSevere sweat HypertensionHypertension

image.google.com

Levels of SeverityLevels of Severity

LaryngospasmLaryngospasm Fractures Fractures Nosocomial Nosocomial

infections infections Bleeding inside the Bleeding inside the

bowels.bowels. Severe may lead to Severe may lead to

death.death. image.google.com

Tetanus surveillance Tetanus surveillance (U.S.)(U.S.)

Approximately 500-600 cases reported per year in the Approximately 500-600 cases reported per year in the late 1940s.late 1940s.

Steadily decreased since 1947Steadily decreased since 1947 Mortality rates declined from 30% to 10% in recent Mortality rates declined from 30% to 10% in recent

years.years.

1. Reported tetanus incidence rates declined from 1980 to 2004.

2. 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 1991-1995 and 1996-2000 were highest among people 40 years of age or older.

2. 28% cases of people younger than 40 years of age during 1991-1995 has increased to 42% from 1996 to 2000.**

**The increase is related to an increased number of injection-drug users (IDU) among younger people.

EpidemiologyEpidemiology

1. Tetanus cases reported worldwide from 1990 to 2004.

2. It is estimated that one million cases reported worldwide.

3. Approximately 300,000-500,000 deaths occurred each year.

Range:

-Dark red= widespread

-Light yellow= few cases

-Gray=no case

PreventionPrevention VaccinationVaccination Recommendation: Recommendation:

One booster every ten years in One booster every ten years in adults.adults.

Administer as a combined vaccine: Administer as a combined vaccine: TDap or DTaP which is against TDap or DTaP which is against diphtheria and pertussis for children diphtheria and pertussis for children less than 7 years old.less than 7 years old.

The TD vaccine (tetanus and The TD vaccine (tetanus and diphtheria) is commonly used in diphtheria) is commonly used in adults and children over seven.adults and children over seven.

TreatmentsTreatments

Clean infected wound.Clean infected wound. Surgical debridement: remove dead and Surgical debridement: remove dead and

infected tissues.infected tissues. Metronidazole treatment: decrease number of Metronidazole treatment: decrease number of

infective bacteria.infective bacteria. Tetanus immune globulin IV or IM.Tetanus immune globulin IV or IM. Tetanus vaccination.Tetanus vaccination.

Treatment for severe Treatment for severe casescases

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, Due to an increase in muscular activity,

maintaining nutrition in the body is required.maintaining nutrition in the body is required.

ReferenceReferenceClostridium tetaniClostridium tetani. 2006. Office of Medical Informatics. College . 2006. Office of Medical Informatics. College

of Medicine. University of Florida. Retrieved on April 29, 2007 of Medicine. University of Florida. Retrieved on April 29, 2007 from from http://medinfo.ufl.edu/year2/mmid/bms5300/bugs/clostet.htmlhttp://medinfo.ufl.edu/year2/mmid/bms5300/bugs/clostet.html

Klein, J. and Ho, W. 2003. Tetanus. Kidshealth. Retrieved on April Klein, J. and Ho, W. 2003. Tetanus. Kidshealth. Retrieved on April 29, 2007 from 29, 2007 from http://www.kidshealth.org/parent/infections/bacterial_viral/tetahttp://www.kidshealth.org/parent/infections/bacterial_viral/tetanus.htmlnus.html

Montecucco, C. and Schiavo, G. 1994. Mechanism of action of Montecucco, C. and Schiavo, G. 1994. Mechanism of action of tetanus and botulinum neurotoxins. tetanus and botulinum neurotoxins. Molecular MicrobiologyMolecular Microbiology. . Vol 13, No 1: 1-8. Vol 13, No 1: 1-8.

Tetanus. 2007. CDC. Retrieved on April 29, 2007 from Tetanus. 2007. CDC. Retrieved on April 29, 2007 from http://www.cdc.gov/Nip/publications/pink/tetanus.pdfhttp://www.cdc.gov/Nip/publications/pink/tetanus.pdf

"Tetanus." 2007. Wikipedia Foundation. Retrieved on May 2, 2007 "Tetanus." 2007. Wikipedia Foundation. Retrieved on May 2, 2007 from from http://http://en.wikipedia.org/wiki/Tetanusen.wikipedia.org/wiki/Tetanus