Bio 54 2002 Schistosomes I: Structure, Infection,

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Bio 54 2002 Schistosomes I Structure,
Infection, Disease

• Pammi Suri, Ph.D.

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Schistosomiasis

• Caused by flatworms/blood flukes of the genus
  Schistosoma
• Major schistosome species infecting humans
• S. mansoni (liver disease)
• S. japonicum (liver disease)
• S. haematobium (urinary bladder disease)
• Public health problem in developing countries
• 200-300 million people infected worldwide
• up to 500,000 immigrants to U.S. infected
• 600 million at risk of infection worldwide

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Schistosomiasis

• Most important worm infection of humans
• is important not because of prevalence ( of
  people infected), rather because of pathogenicity
  (severity of disease caused)
• Debilitating/potentially fatal disease
• 500,000-600,00 deaths per year worldwide
• Major cause of liver bladder diseases in
  developing countries
• Much of the diseases is caused by host immune
  responses to eggs produced by the worm

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HISTORY OF SCHISTOSOMIASIS

• Most ancient of proven infections, having been
  found in mummies in both Egypt and China dating
  back to 1250 BC
• In Egypt, schistosomiasis has been a major
  disease in association with the Nile River
• Prevalence exceeds 80 in some areas
• Historical note in traditional Egyptian culture,
  when a boy began to pass blood in his urine (due
  to chronic S. haematobium infection), he was
  considered a man (equivalent to female
  menstruation)
• In China - Chairman Mao called schistosomiasis
  the Plague Spirit and launched a nationwide
  effort to eradicate it
• S. japonicum infection remains the single most
  serious disease in China (about 15 million are
  currently infected)
• Parasite first observed by Theodor Bilharz in
  1852, thus the disease has also been called
  Bilharziasis
• S. mansoni infection was established in the
  Western Hemisphere as a result of the slave trade

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TAXONOMY
Recall that the filarial worms which we have
previously studied are members of an entirely
different phylum (Nematoda)
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The Global Distributionof Schistosoma mansoni

• S. japonicum is found primarily in China,
  Malaysia, and the Philippines
• S. haematobium is found in parts of Africa, the
  Middle East, and southwestern India

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Infection is Acquired by Contact with
Contaminated Fresh Water
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The Life Cycle ofSchistosoma mansoni
The life cycles of S. japonicum and S.
haematobium are generally similar to that of S.
mansoni, except that in S. haematobium infections
the adult worms inhabit the venus plexus
surrounding the urinary bladder and eggs are
excreted in the urine
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Exposure to sunlight
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MIRACIDIUM
miracidium 0.15 mm

• Ciliated free-swimming form released from egg
  upon hatching
• Miracidium locates and penetrates intermediate
  host (specific freshwater snail species)
• Anterior papilla of the miracidium snakes its way
  through snail like a probe
• The papilla digests snail tissue and facilitates
  miracidium entry into the snail
• Upon penetration, the miracidium loses its cilia
  and transforms into a mother sporocyst

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MIRACIDIUM
miracidium 0.15 mm

• within the hepatopancreas of the snail, the
  mother sporocyst produces multiple daughter
  sporocysts by asexual reproduction
• Daughter sporocysts produce cercariae
• A single miracidium can ultimately give rise to
  4000-5000 cercariae of a single sex in about 21
  days
• snail growth is stunted as a result of infection
  and miracidial burden on snails often results in
  death of this host, but not before thousands of
  cercariae have been released

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CERCARIA

• fork-tailed free swimming infectious form, 0.5mm
  in length, which is released from the infected
  snail upon exposure to sunlight
• A cercaria can be genetically male or female
  (although the external morphology is identical)
• positively phototropic (move towards light) and
  negatively geotropic
• natural tendency to cluster at the surfaces of
  water, which facilitates contact with definitive
  host
• also uses temperature gradients and chemotaxis to
  locate its definitive host

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CERCARIA

• outer covering (the Glycocalyx) is composed of
  complex carbohydrates which gives tensile
  strength and serves as an osmotic barrier
• Glycocalyx is shed upon penetration of the host
  skin.
• Antibodies to glycocalyx polysaccharides can be
  used as a diagnostic test to establish that
  infection has occurred.
• The cercarial tegument is a trilaminar plasma
  membrane that is devoid of subcellular organelles
  prior to transformation to the schistosomula form

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CERCARIA
head
tail

• infects human host by penetrating intact skin
• enters through sebaceous ducts, hair follicles,
  etc.
• There is no pain or other sensation during
  cercarial penetration, although cercarial
  dermatitis may occur 1-2 days after infection
• Produces several proteases which are important to
  parasite invasion, e.g. Hyaluronidases,
  Collagenases other BM enzymes
• The cercaria loses its tail upon penetration
• the head portion (schistosomula) penetrates the
  tissues and adapts to a parasitic existence
  within the human host, ultimately developing into
  an adult worm

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Schistosomula

• Transitory, but important, life cycle phase
• process of penetration of host tissue and
  subsequent migration through tissues is protease
  dependent
• Following penetration, remains in the skin for
  about 2 days, then enters the bloodstream
• Follows venous blood flow to the lungs,
  traversing the lung capillary beds (within 5-8
  days)
• Returns to the heart, then systemic circulation,
  and localizes to hepatic portal system (liver)
• Over the next 3 weeks, schistosomula mature into
  adult worms, pair, and migrate from the liver,
  ultimately lodging in mesenteric veins
  surrounding the intestine

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S. mansoni Adult Worms
male

• Male
• 1 cm long x 1 mm wide
• prominent ventral groove
• tegumental tuberculations
• Female
• 1.5 cm long x 0.2 mm wide
• produces 300 eggs per day
• The Worm Pair
• continuous copulation
• Average life span 5-8 years
• gt500,000 total eggs/pair
• can live 25-30 years

female
male
female
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ADULT WORMS

• attach and move in the host using suckers
• Reproduce (i.e. have sex and produce eggs), but
  do not multiply (increase their numbers) within
  the human host
• Thus the number of adult worms in an individual
  cannot exceed the number of cercariae that
  penetrate the skin
• Exist as separate male and female worms, mate in
  liver and stay in copulation for rest of their
  lives
• mating is a prerequisite of female development
• unpaired adult female is stunted and will not
  produce eggs, thus will not cause disease
• paired worms migrate to vessels feeding
  intestines
• Female schistosomes lay eggs throughout their
  lives

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Effects of proper mating on female development
and sexual maturity
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OVUM (EGG)

• S. mansoni and S. haematobium females produce
  300 eggs/day S. japonicum up to 3000 eggs/day
• Thus an individual with 50 mated pairs is exposed
  to 15,000-150,000 new eggs every day, depending
  on the parasite species
• eggs are passed through the posterior suckers of
  the female worm attached to host tissue
• eggs penetrate gut or bladder wall and are
  excreted with feces (S. mansoni, S. japonicum )
  or urine (S. haematobium )
• eggs hatch when shed into fresh water and release
  miracidia
• eggs can also be back-deposited into vessel
  system feeding liver, causing immune reactions
  that result in liver pathology
• It is important to note that almost all of the
  pathology caused by schistosomes results from
  host reaction to the eggs, NOT the adults which
  produce them

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A Comparison of Schistosome Eggs
S. mansoni Lateral spine
S. haematobium Terminal spine
S. japonicum No spine
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Disease Spectrum (Acute)

• Cercarial dermatitis (swimmers itch)
• Reaction to cercariae in the skin that develops
  within 24 hours of exposure
• Causes itchy rash that usually subsides within 3
  days
• Katayama fever
• Most commonly observed in heavy S. japonicum
  infections
• Acute immune reaction that begins 2-3 weeks after
  exposure and lasts 1-2 months
• Causes fever, chills, eosinophilia, cough, and
  temporary enlargement of lymph nodes, spleen, and
  liver
• Acute disease is mediated by parasite antigens
  (derived from cercaria, schistosomula,
  juvenile worms), but probably not by egg
  antigens, since acute symptoms typically begin
  before worms become sexually mature

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Cercarial Dermatitis
Rat abdominal skin 3 days post infection
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Disease Spectrum (Chronic)

• Unlike acute disease, chronic disease is caused
  primarily by eggs, not by the worms themselves
• Hepatosplenic
• Egg-induced liver fibrosis (scarring) causes
  obstruction of hepatic blood flow, leading to
  portal hypertension with subsequent enlargement
  of liver and spleen
• Intestinal
• Eggs in the intestinal wall cause lesions that
  result in abdominal pain, cramping, and bloody
  stools
• Bladder (S. haematobium only)
• Bladder and ureter can become damaged, leading to
  hematuria (bloody urine) and dysuria (difficulty
  in urination)
• Pulmonary
• Eggs may deposit in the lungs, causing
  inflammation and pulmonary obstruction, leading
  to heart disease
• Central Nervous System
• Eggs may deposit in the brain and spinal cord,
  causing neurological problems

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Pathogenesis of Schistosomiasis mansoni
The preferred route
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Liver Pathology

• Caused primarily by S. mansoni and S. japonicum
  infections
• Due to eggs trapped in pre-sinusoidal venules of
  liver
• inflammatory cell-mediated response to soluble
  egg antigens results in granuloma formation
  around the egg
• leads to numerous immunological abnormalities
• Paradoxically, these may help protect the host
  from developing even worse disease!
• Causes tissue damage and scarring, with
  subsequent blood vessel obstruction that leads to
  hepatomegaly
• Very little disease is caused by the adult worms,
  which are apparently refractory to immune attack
• In many cases liver disease develops silently and
  symptoms only begin once major damage has occurred

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The Schistosome Granulomaan inflammatory
reaction that surrounds eggs that are deposited
in the tissues

• Eosinophils
• Macrophages
• T cells
• B cells
• Neutrophils
• Plasma Cells
• Mast Cells
• Fibroblasts

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Pipestem Liver Fibrosisscarring around
hepatic blood vessels due to egg deposition,
leading to narrowing of the vessel lumen
Consequences

• Obstruction of hepatic blood flow
• Portal hypertension
• Enlargement of collateral blood vessels
  (Abdominal, Esophageal) due to shunting of blood
  flow
• Enlarged collateral vessels may rupture, causing
  massive bleeding
• Hepatosplenomegaly
• Liver failure

Cross-section of liver from an S. mansoni
infected human
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Chronic Schistosomiasis
Hepatosplenomegaly with buildup of abdominal
fluid (ascites) and severe wasting
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Urinary Tract Pathology

• Caused primarily by S. haematobium
• Egg deposition in the bladder wall leads to
  sandy patches, ulceration, and lesions
• Major symptoms
• Hematuria (blood in the urine)
• Dysuria (difficulty in urination)
• Obstruction of urine flow from the kidney to the
  bladder may cause obstructive renal disease
• Bladder cancer may eventually arise in areas of
  heavy egg deposition

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DIAGNOSIS

• worm burden is a major determinant of disease
• Light infections are usually asymptomatic
  (although silent tissue damage does occur),
  whereas heavy infections tend to cause serious
  pathology and clinical symptoms
• Intensity of infection can be determined by
  counting eggs passed in urine or feces
• Complication in advanced cases egg output may be
  reduced, although eggs are still being deposited
  in the tissues
• Host antibody response to cercarial glycocalyx or
  other parasite antigens can be used as an
  immunological test
• Antigens secreted by adult worms (such as
  Circulating Cathodic Antigen CCA) can also be
  detected
• Liver/Bladder pathology may be detected using
  ultrasound scanning or standard X-ray based
  techniques

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TREATMENT CONTROL

• Chemotherapy with drugs such as PRAZIQUANTEL or
  OXAMNIQUINE is highly effective against adult
  worms, often requiring only a single dose for
  complete cure
• Complication reinfection is common, especially
  in areas of high endemicity
• Snail control using molluscicides to remove the
  source of cercariae
• Complications requires sustained effort,
  expensive, and can be environmentally problematic
• Sanitation to prevent contaminated feces/urine
  from contacting fresh water
• Complication developing countries often do not
  have the resources to provide sanitary facilities
  to all their citizens
• Vaccination
• Despite a concerted effort, no vaccine is
  currently available