Mycobacterium leprae

Dr. Hala Al Daghistani

Mycobacterium leprae, the cause of leprosy, is an acid-fast bacillus that has not been grown in artificial medium or tissue culture. However, it can be grown in the footpads of normal mice, and in the armadillo, which may also be infected naturally. Its growth in animals is very slow, with an estimated “Doubling time “of 12 to 14 days.

Leprosy Leprosy is a chronic granulomatous disease of the peripheral nerves and superficial tissues, particularly the nasal mucosa. Disease ranges from slowly resolving anesthetic skin lesions to the disfiguring facial lesions responsible for the social stigma اجتماعية .of the individuals with leprosy (lepers) وصمة

Epidemiology The exact mode of transmission is unknown but appears to be by

generation of small droplets from the nasal secretions from cases of lepromatous leprosy.

Traumatic inoculation through minor skin lesions or tattoos is also possible.

The central reservoir is infected humans. Biting insects may also be involved

The incubation period as estimated from clinical observations is generally 2 to 7 years but sometimes up to 4 decades. The infectivity of M. leprae is low. Most new cases have had prolonged close contact with an infected individual..

It was estimated that 10 million infected persons are present in Asia, Africa, and Latin America.

PathogenesisM. leprae is an obligate intracellular parasite that must multiply in host cells to persist. In humans the preferred cells are macrophages and Schwann cells. Specific “Phenolic GlycoLipid-1“ (PGL-1) and “LipoArabino Mannan” (LAM) have been implicated in the ability to survive and multiply in these cells. The organism may invade peripheral sensory nerves, resulting in patchy anesthesia.

In tuberculoid leprosy, few M. leprae are seen in tuberculoid lesions, which are granulomatous with extensive epithelioid cells, giant cells, and lymphocytic infiltration.

In lepromatous multibacillary leprosy, CMI is deficient, and growth of M. leprae is, relatively unimpeded. Histologically, lesions show dense infiltration with leprosy bacilli, and large numbers may reach the bloodstream.

Phenolic GlycoLipid (PGL), is responsible for reprogramming the macrophages and helps the bacteria establish infection by escaping macrophage defenses.    

M. leprae-infected macrophages can settle on the fibers and injure the nerve cells and myelin sheaths. PGL triggers this destructive response in infected macrophages by causing the cells to overproduce Nitric oxide. Nitric oxide enters the nerve, where it damages mitochondria and destroys myelin sheaths.

ImmunityImmunity to M. leprae is CMI mediated. The range of disease correlates with DTH responsiveness to lepromin, a skin test antigen derived from leprous tissue similar to tuberculin.Tuberculoid cases have minimal disease and positive skin tests. Lepromatous cases have progressive disease and negative skin tests.

L E P R O S Y: C L I N I C A L A S P E C T STuberculoid LeprosyTuberculoid leprosy involves the development of macules or large, flattened plaques on the face, trunk, and limbs, with raised, erythematous edges and dry, pale, hairless centers. When the bacterium has invaded peripheral nerves, the lesions are anesthetic.

Lepromatous LeprosyIn lepromatous multibacillary leprosy. A large numbers may reach the bloodstream. Skin lesions are extensive, symmetric, and diffuse, particularly on the face, with thickening of the looser skin of the lips, forehead, and ears. Damage may be severe, with loss of nasal bones and septum, sometimes of digits, and with testicular atrophy in men.

DiagnosisLaboratory diagnosis of lepromatous leprosy involves preparation of acid-fast stained scrapings of infected tissue, particularly nasal mucosa or ear lobes. Large numbers of acid-fast bacilli are seen. PGL-1–based serologic tests have been evaluated for their usefulness in serodiagnosis.

Clostridium tetani

C. tetani is a slim, Gram-positive rod, forms spores readily in nature and in culture, yielding a typical round terminal spore that gives the organism a drumstick appearance before the residual vegetative cell disintegrates. The organism is flagellate and motile. C. tetani requires strict anaerobic conditions.C. tetani spores remain viable in soil or culture for many years. It is resistant to most disinfectants and withstands boiling for several minutes.The most important product of C. tetani is its neurotoxic exotoxin, tetanospasmin or tetanus toxin, a metalloproteinase that enzymatically degrades a protein required for docking of neurotransmitter vesicles at the appropriate site on presynaptic membranes. Loss of this function prevents release of neurotransmitters used by inhibitory afferent motor neurons, generating spasms. The toxin is heat labile, antigenic, readily neutralized by antitoxin, and destroyed by intestinal proteases.

Tetanus The important feature of tetanus is severe muscle spasms (or “lockjaw”

when the jaw muscles are involved). This occurs despite minimal or no inflammation at the primary site of

infection The disease is caused by in vivo production of a neurotoxin that acts

centrally, not locally.

EPIDEMIOLOGY The spores of C. tetani exist in many soils, and the organism is sometimes

found in the lower intestinal tract of humans and animals.

The spores are introduced into wounds contaminated with soil or foreign bodies. The wounds are often quite small, (eg, a puncture wound with a splinter).

In many developing countries, the majority of tetanus cases occur in recently delivered infants when the umbilical cord is bandaged in a nonsterile manner.

PATHOGENESIS The usual predisposing factor for tetanus is an area of very low oxidation–

reduction potential in which tetanus spores can germinate Tetanus bacilli multiply locally and neither damage nor invade adjacent

tissues. Tetanospasmin is elaborated at the site of infection and enters the presynaptic terminals reaching the CNS.

In the spinal cord, its blockage of postsynaptic inhibition of spinal motor reflexes produces spasmodic contractions of the muscles.

T E TA N U S : C L I N I C A L A S P E C T SThe incubation period of the disease is from 4 days to several weeks. The shorter incubation period is usually associated with wounds in areas supplied by the cranial motor nerves, probably because of a shorter transmission route for the toxin to the CNS.

The diagnosis is clinical; neither culture nor toxin testing are useful. The masseter muscles الماضغة are often the first to be affected, resultingالعضلةin inability to open the mouth properly (trismus); this effect accounts for the use of the term lockjaw to describe the disease. As other muscles become affected, intermittent spasms can become generalized to include muscles of respiration and swallowing. Untreated patients with tetanus retain consciousness and small stimuli can trigger massive contractions. In fatal cases, death results from exhaustion and respiratory failure. Untreated, the mortality caused by the generalized disease varies from 15 to more than 60%, according to the lesion, incubation period, and age of the patient. Mortality is highest in neonates and in elderly patients.

TREATMENT Specific treatment of tetanus involves neutralization of any unbound toxin

with large doses of human tetanus immune globulin (HTIG), which is derived from the blood of volunteers hyperimmunized with toxoid.

The value of antimicrobics is not clear because toxin binding is irreversible

PREVENTION Routine active immunization with tetanus toxoid, combined with diphtheria

toxoid and pertussis vaccine (DTaP) for primary immunization in childhood and DT for adults, can completely prevent the disease

Five doses of DT are recommended, to be given at the ages of 2, 4, 6, and 18 months, and once again between the ages of 4 and 6 years.

Thereafter a booster of adult-type tetanus diphtheria toxoid should be given every 10 years.

immunization efforts have been focused on pregnant women, because transplacental transfer of antibodies to the fetus also prevents the highly lethal neonatal tetanus.

Unimmunized subjects with tetanus-prone wounds should be given passive immunity with a prophylactic dose of HTIG as soon as possible. This immunization provides immediate protection.

Clostridium botulinum

C. botulinum is a large Gram-positive rod much like the rest of the clostridia. Its spores resist boiling for long periods, and moist heat at 121°C is required for certain destruction.

Germination of spores and growth of C. botulinum can occur in a variety of alkaline or neutral foodstuffs when conditions are sufficiently anaerobic.

Botulinum toxin is the most potent toxin known in nature, with an estimated lethaldose for humans of less than 1 ng. Like tetanospasmin, botulinum toxin is a metalloproteinase that acts on the presynaptic membranes at neuromuscular junctions. The major effect is blockage of acetylcholine release and paralysis of the motor system. It also causes dysfunction of the autonomic nervous system.

C. botulinum is classified into multiple types (A to G) based on the antigenic specificity of the neurotoxins. All of the toxins are heat labile and destroyed rapidly at 100°C but are resistant to the enzymes of the gastrointestinal tract.

B O T U L I S MBotulism begins with cranial nerve paralysis and develops into descending symmetrical motor paralysis, which may involve the respiratory musclesNo fever or other signs of infection occur.The time course depends on the amount of toxin present and whether it was ingested preformed in food or produced endogenously in the intestinal tract or a wound.

EPIDEMIOLOGYSpores of C. botulinum are found in soil, pond, and lake sediments. If spores contaminate food, they may convert to the vegetative state, multiply, and produce toxin in storage under proper conditions. This may occur with no change in food taste, color, or odor. The alkaline conditions provided by vegetables, mushrooms and fish support the growth of C. botulinum, and the acidic conditions such as canned fruit do not support the growth of the bacterium. Because the toxin is heat labile, food must be ingested uncooked or after insufficient cooking.

PATHOGENESISFood-borne botulism is an intoxication, not an infection. The ingested preformed toxin is absorbed in the intestinal tract and reaches its neuromuscular junction target via the bloodstream. Once bound there, its inhibition of acetylcholine release causes paralysis due to lack of neuromuscular transmission. The specific disease manifestations depend on the specific nerves to which the circulating toxin binds.Cardiac arrhythmias and blood pressure instability are believed to be due to effects of the toxin on the autonomic nervous system.

B O T U L I S M : C L I N I C A L A S P E C T SFood-borne botulism usually starts 12 to 36 hours after ingestion of the

toxin. The first signs are nausea, dry mouth, and, in some cases, diarrhea. Cranial nerve signs, including blurred vision, pupillary dilatation, and

nystagmus الالارادي السريع المقلتين occur later , تذبذب Symmetrical paralysis begins with the ocular, laryngeal, and respiratory

muscles and spreads to the trunk and extremities. The most serious finding is complete respiratory paralysis. Mortality is 10 to 20%.

Infant BotulismInfant botulism results when the toxin is produced endogenously.A syndrome associated with C. botulinum that occurs in infants between the ages of 3 weeks and 8 months The organism is apparently introduced on weaning or with dietary supplements, especially honey, and multiplies in the infant’s colon, with absorption of small amounts of toxin. The infant shows constipation, poor muscle tone, lethargy, and feeding problems and may have ophthalmic and other paralyses similar to those in adult botulism.

Wound BotulismVery rarely, wounds infected with other organisms may allow C. botulinum to grow. Wound botulism in parenteral users of cocaine (contamination of wounds with spores that germinated and the toxin absorbed systematically)

Disease similar to that from food poisoning may develop, or it may begin with weakness to the injured extremity.

LABORATORY DIAGNOSIS

TREATMENT AND PREVENTION The administration of large doses of horse C. botulinum antitoxin is thought

to be useful in neutralizing free toxin. Frequent hypersensitivity reactions related to the equine origin of this preparation makes it unsuitable for use in infants.