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Parasitology and entomology > Schistosomes, immunology, and control > Flashcards

Schistosomes, immunology, and control Flashcards

1
Q

Describe the lifecycle of schisto.

A

Eggs shed in human faeces or urine –> eggs in water hatch to release miracidia –> miracidia penetrate snails (intermediate host) –> sporocysts develop in snails –> cercariae are released from the snail –> cercariae lose tails as they penetrate human skin and are schistosomula at this stage (definitive host) –> enter human circulation –> migrate to the portal blood and liver and mature into adults –> adult worms pair and migrate to -mesenteric venules of bowels (eggs circulate to the liver and are shed in stool), or -venous plexus of bladder (eggs shed in urine).

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2
Q

What are the three most common schistosomes? Where are they most commonly found?

A
  • Schistosoma mansoni -Sub Saharan Africa, Pacific coast of S America (slave trade associated)
  • S haematobium- Sub Saharan Africa
  • S japonicum- Asia
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3
Q

Where is S intercalatum found?

A

West and Central Africa.

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4
Q

Where are the two main bodily locations, and why, for schisto pathology

A
  • Urogenital
  • Intestinal/hepatic

This is where the pathology occurs not actually where the worms are.

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5
Q

Which two schistos are strongly associated with the river Nile?

A

Mansoni and haematobium. (Most are associated with rivers, oases or man made irrigation systems, and from people being in contact with water).

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6
Q

What are the intermediate hosts for schisto?

A

Bulnius- haematobium

Biomphlaria- mansoni

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7
Q

Describe the Japanese study elucidating the method of transmission of schisto.

A

Covered cows mouth (/stopping them drinking)or legs. Cows who drank the water but had their legs covered did not get infected. Elucidated percutaneous infection.

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8
Q

Where are paired schistosomes located? How do they maintain their position here?

A

Are blood flukes so are found in blood vessels. Use suckers to attach to endothelial wall.

Haematobium has a tropism for the vessels in the vesicle plexus and japonicum and mansoni for the vessels near the intestine.

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9
Q

What are the differences in tegument of haemotobium and japonicum?

A

Haematobium is rough, japonicum is smooth.

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10
Q

Which vessels are mansoni, haematobium and japonicum found?

A

Mansoni- mesenteric vein
Haeatobium- vesical (near lower bladder) and pelvic plexus
Japnonicum- in the branches between the large and small intestine.
These locations are where the females produce eggs.

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11
Q

What is the route of eggs when produced by the mothers in the blood vessels?

A

Eggs penetrate endothelium and then the gut wall to be excreted in faeces (then hatch in water etc).

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12
Q

Describe the route following skin penetration by cercariae to infection of snail.

A

Swept through lungs by blood –> end up in the portal system –> pair up (m and f) –> migrate to the bowel –> excreted in faeces/ urine–> miracidia form from eggs in water –> meracidia penetrate snail tissue.

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13
Q

What are the intermediate hosts?

A

Always gastropod molluscs.

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14
Q

Describe infection of the snail.

A

Meracidia penetrate the foot of the snail –> develop into mother sporocysts in the mantle –> daughter sporocysts are produced –> daughter sporocysts move to the digestive gland and develop –> cercariae.

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15
Q

What are the intermediate host snails for Haematobium, japonicum and mansoni?
What does the number of cercariae produced by each species depend on?

A

Haematobium (and intercalatum)- bulnius snail
Mansoni biomphalaria
Japonicum- oncomelania hupensis
Size of snail determines the number of cercariae.

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16
Q

Describe the eggs of the three main species.

A

Mansoni- 140µm, lateral spine
Haematobium- 150µm with a terminal spine
Japonicum-85µm (smaller) with a rudimentary spine

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17
Q

How long do eggs take to hatch in water?

A

Around 6 days after being laid.

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18
Q

For how long after being laid are eggs viable?

A

2-3 weeks.

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19
Q

How do miracidia find snails to infect? How do they penetrate the snail?

A

Have hairs to swim quickly through the water. Use chemoreceptors to chemosense carbohydrates in the snail slime.

Use proteolytic enzymes.

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20
Q

When do cercariae shed?

A
  • Mansoni- during the day: because sunlight this peaks in the middle of the day so targets humans
  • Japonicum- is mainly zoonotic so peaks at night to target animal hosts.
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21
Q

How long do cercariae remain viable for after shedding?

A

48 hours.

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22
Q

Describe cercariae features

A
  • Bifurcated tail to swim both ways
  • Head with lots of glands for penetration
  • Chemoreceptors to detect lipids and fatty acids on human skin etc.
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23
Q

Describe the process of penetration by cercariae.

A
  • Penetrate skin in about 1 minute
  • Tail drops off as they penetrate and glycocalyx is shed
  • Transform into schistosomula in the epidermis.
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24
Q

Describe what happens after the cercariae form a schistosomula in the epidermis

A

They find blood vessels –> go through the circulation to the lungs –> penetrate lung capillaries –> some make it into the portal system –> develop and pair up in the liver –> move in pairs to the final site where they swim against the blood flow to the plexus or mesenteric vein.

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25
Q

How many eggs per ay does japonicum produce?

A

3000, this is very high. Egg output depends on the species.

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26
Q

How do the eggs get into the faeces to be excreted?

A

Must penetrate the intestinal wall, they must cross the mucosal wall - a lot of eggs get stuck at this point but it doesn’t matter as egg production is so high.

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27
Q

Although eggs getting stuck while penetrating does not matter to the worm, describe how this matters for the human.

A

Causes inflammation as they get stuck in the liver and bladder and so the host response to these stuck eggs is what generates pathology.

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28
Q

What are miracidia?

A

Live larvae inside the egg, or can be the free-swimming ciliated larval stage.

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29
Q

What are the three ways in which pathology presents?

A
  • Dermatitis
  • Katayama fever (acute schistosomiasis)
  • Chronic schistosomiasis
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30
Q

What is “swimmers itch”? This causes the dermatitis pathology.

A

A hypersensitivity reaction usually produced by the penetration of avian schistosomiasis into skin, is transient.
Dermatitis pathology is usually seen with non-human schistos and dermatitis caused by human schistos is rare.

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31
Q

Describe acute schisto infection.

A

Produces katayama fever. Occurs 3-8 weeks post infection when worms mature and produce eggs. A hypersensitivity reaction to the eggs produces a general inflammatory reaction and eosinophilia.

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32
Q

Describe the presentation of chronic schisto

A

This is the main public health problem.
There is an immune response to eggs stuck in tissue, as well as tissue damage from the eggs migrating through.
Can be ectopic and affect the lungs, CNS, genital tract

AS well as the inflammation, we see ulceration, the conbination of the two causes chronic haemorrhage of mucosal surfaces, mucosal thickening and polyps formation (abnormal tissue growth).

Fibrosis from inflammatory recruitment of fibroblasts.

Eggs dying off get calcified.

These cause hepatosplenomegaly. This causes portal hypertension as blood cannot go through the liver as well.

Gastric and oesophagus vein pressure also increases as a result. This varies in form and may cause acute/ internal bleeding due to blood vessels bursting. Can cause haematemesis (vomiting blood).

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33
Q

Describe the inflammatory response seen in chronic schisto.

A

Strong immune response to stuck eggs produces a granuloma (lymphocytes, macrophages, eosinophils, fibroblasts) and strong TH2 cytokine response.
Although granulomas fade over time as the eggs die, the fibrosis produced is irreversible.

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34
Q

What happens to eggs as they die off when stuck?

A

They calcify/mineralise.

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35
Q

Which schisto species is the most pathogenic and why?

A

Japonicum as it produces the largest numbers of eggs so more get trapped and hence cause pathology quicker.

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36
Q

Why may antihelminthic treatment not be very effective in the late stage?

A

Because fibrosis and damage have already occurred.

37
Q

What is a caput medusae?

A

Caput medusae is the appearance of distended and engorged superficial epigastric veins, almost always caused by portal hypertension.
(Is collateral formation between the portal and epigastric veins)

38
Q

What is the morbidity in 10% of patients (when risk of mortality is 1%)?

A
  • Anaemia
  • Organ damage
  • Co-infections
  • Disability
  • Malnutrition.
39
Q

Which species causes urogenital schisto?

A

Haematobium

40
Q

What are the products of urogenital schisto?

A
  • Blood in urine
  • Calcification and tissue fibrosis (lesions in bladder wall from calcifying eggs) (entire bladder wall can become calcified). Ureter can be permanently dilated or smaller due to calcification
  • Bladder and kidney issues. Ascending bacterial infection can affect the kidney.
  • Increased risk of bladder cancer due to inflammation (squamous metaplasia–> carcinoma)
  • Polyp formation in bladder wall.
  • Marked mucosal swelling
  • Loss of protein- proteinemia (e.g. protein lost in urine)
41
Q

Which bladder cancer is common in schisto (haematobium)?

A

Squamous cell carcinoma of the bladder.

42
Q

What can pulmonary hypertension as a result of ectopic schisto cause in terms of the heart?

A

Right ventricular hypertrophy and failure. (Common with mansoni and haematobium, rare in japonicum as the eggs are smaller so don’t get stuck in the lungs)

43
Q

What occurs in ectopic schisto to the CNS?

A

Granulomas in the spinal cord from eggs and adults being present can cause paraplegia.
Epilepsy if go into the brain (japonicum)

44
Q

Describe who is affected by genital schisto and by which species. How does it present?

A

3/4 if females with haematobium have schisto in the uterus, cervix or vagina.
Present as sandy patches (granuloma), vascularisation and contact bleeding.
Commonly misdiagnosed. There is a link to HIV infection.

Men also get it- 50% of haematobium infected males have eggs in their semen. IF they get stuck in the scrotum/ lymphatics, scrotal elephantiasis occurs.

45
Q

How do we diagnose schisto?

A

May take years to develop a clear pathology so diagnosis is hard.

  • Chronic diarrhoea
  • Abdominal pain
  • Anaemia
  • Hepatosplenomegaly
  • Eosinophilia
  • Parasitology looking for eggs in semen, urine, faeces
  • Use morbidity markers such as blood in faeces or in urine.
  • Immunoassays like ELISA
  • Antigen detection
46
Q

What are the morbidity markers for schisto

A

-Blood in urine or faeces

47
Q

Which antigen do we look for in antigen detection diagnosis of schisto?

A

Circulating cathodic antigen (a proteoglycan antigen secreted by adult worms).

48
Q

How do we treat schisto?

A

PZQ

49
Q

How does PZQ work? What is the recommended dose?

A

Causes a calcium influx into the parasite which causes paralysis and death.
40mg/kg recommended but 60 is better.

50
Q

Why/how is the paediatric formulation of PZQ better?

A
  • Water soluble
  • Smaller
  • Taste better

Entered phase III study.

51
Q

How do we control schisto?

A

Education, sanitation (build latrines), water supply, snail control, chemotherapy campaigns, concrete irrigation canals (minimise vegetation for snails), mollusciciding (ecosystem downsides), night soil fermenter (provides methane gas as an incentive, replacement of cattle with tractors, fence bovines away from waterways, ferment buffalo excrement, nightsoil collection,

52
Q

What is the effect of PZQ on its own?

A

On its own it does not reduce population prevalence however it does reduce individual morbidity.

53
Q

Drug resistance?

A

Easily induced in the lab, some reports of human treatment failure but not sure if this is actually resistance, may be due to low doses which suppress egg production which only has a transient effect. We need more sensitive detection and new drugs before PZQ resistance becomes a problem.

54
Q

What percentage of people develop severe morbidity from infection and how many die?

A

10%, 1%

55
Q

Where do mansoni eggs get stuck?

A

Either get trapped in the intestine wall as they migrate or are get carried by the blood and get lodged in the liver.

56
Q

Why is pathology immune mediated? (Bonus: which immune cells are recruited?)

A

They get lodged in tissues which produces an immune response against them and this causes pathology as immune cells recruited are macrophages, lymphocytes, neutrophils, eosinophils and fibroblasts- this causes inflammation and permanent fibrosis.

57
Q

Which immune cells are recruited last during granuloma?

A

Fibroblasts, they are what produce fibrosis by depositing collagen.

58
Q

What is periportal fibrosis and how does it happen during schisto infection?

A

It is the fibrosis occurs in the liver by eggs gettings stuck and stimulating a fibrotic response. This causes blockage of blood flow in the liver which causes portal hypertension. hepatosplenomegaly, ascites (build up of fluid in the abdomen), and collateral circulation (alternative circulation where circulation is blocked so is diverted e.g. through smaller blood vessels). This in turn leads to oesophagal varices (enlarged veins) and haematemesis (vomiting blood).

59
Q

Which type of T cell is responsible for the granuloma formation from trapped eggs? How was this elucidated? What happens in the absence of these T cells?

A

Mediated by CD4+ T cells. Elucidated because T cell-deficient mice had no granulomas, and depleting CD4+ T cells gave smaller granulomas. Without CD4 T cells to produce granulomas, we get necrosis of the tissue instead, and massive tissue disruption and cell death.

60
Q

It is known that it is the antigens on the schistosome eggs that induce the inflammatory response. Which antigen is the main one that provokes this response and how is the response measured (i.e. which type of response is produced/ which cytokines)?

A

Secreted ribonuclease omega 1.
Produces a strong TH2 response which produces lots of IL5, IL13 and IL4 (typical TH2 response).
Also a lot of IL10 is also produced which is a regulatory cytokine.
Some IFN gamma is produced but the response is predominantly TH2.

61
Q

Which TH2 cytokines are produced during granuloma formation and what happens when we knock out two of these?

A

IL4, IL5 and IL13. If you KO IL4 and IL13, we get necrosis and death in mouse models.

62
Q

Therefore, which cytokines are needed for granuloma formation? What is the evidence for your choice of cytokines?

A

IL4 and IL13. Double KOs do NOT produce granulomas.
Both must be present.
Single KOs DO give granuloma (some level of redundancy)
IL5 is NOT responsible for granuloma formation as KO of this still produces granuloma.

63
Q

Which cytokine is responsible for fibrosis and what is the evidence?

A

KO of IL4= collagen production
KO of IL13= NO collagen production.
Therefore itis IL13 alone that stimulates and activate fibroblasts to drive fibrosis.
There is a strong correlation between level of IL13 and severity of periportal fibrosis.

64
Q

SOME IFN gamma is being produced in the liver, which T cell response suppresses this?

A

TH2 suppresses IFN gamma and vice versa.

65
Q

What happens when we treat mice to neutralise/ remove IFN gamma? What can be deduced from this?

A

Granulomas get MUCH bigger. This effect is also seen using an antibody to neutralise IL12, the main stimulator of IFN gamma.
Therefore IFN gamma must be protecting against excessive fibrosis.
IFN gamma counteracts the TH2 response (which is IL13, IL4 and IL5 which work to stimulate the production of granuloma).

66
Q

Hepatic fibrosis and portal hypertension has a familial/ genetic aspect. Which gene did gene segregation analysis show to be responsible for this?

A

The gene SM2 which codes for the IFN gamma receptor (R1)! This gene influences hepatic fibrosis.

A second polymorphism was also found and was in the IFN gamma gene itself- specific mutations in this were associated with higher/lower risks of fibrosis.

67
Q

What occurs when there is too much IFN gamma?

A

A too strong TH1 response producing lots of IFN gamma is highly pathogenic and produces a highly inflammatory response in the liver which leads to necrosis.

68
Q

KO of which cytokines can highly skew an immune response towards TH1?

A

IL10 and IL4 double KO.
This can cause a hepatotoxic response when infected with schisto as too much inflammation is produced.
It causes lots of NO production, lots of IFN gamma and TNF.
=quick death

69
Q

KO of which cytokines can skew an immune response to TH2?

A

IL10, IL12 double KO increases mortality and skews the response to TH2, however the death is slower than if skewed to TH1. (IL10 regulates away from TH1 and towards TH2)
Skewing either way leads to singificant pathology thta leads to death over time.

70
Q

What is the funciton of IL10?

A

Regulates both TH1 and 2, stop a strong skew of the response.

71
Q

What mediates the shrinking of a granuloma from the acute phase to the chronic phase?

A

IL10 regulate cytokines that mediate the shrinking of the granuloma.

72
Q

What is the product of an IL10 KO?

A

Granuloma gets bigger over time and does not shrink as it should. Causes mice to start dying in this chronic state.

IL10 significantly reduces the level of granuloma pathology.

73
Q

What is the balance of cytokines in severe fibrosis?

A

Lots of IL13 produced but not enough IL10 to control. This is inverse in less severe fibrosis.
More IL13 = greater fibrosis
More IL10= less fibrosis.

74
Q

When does schisto prevalence and intensity peak?

A

During adolescence. This might be explained by the patterns in water contact increasing in adolescence.

75
Q

Do we see immunity to schisto?

A

See some level of naturally acquired immunity in endemic areas however it is NOT sterile immunity. Get some level of resistance to infection.

Lower rates in community with age. Water pattern should show the same pattern but this is not the case. This suggests the development of immunity.

76
Q

Describe the immunological correlation with reinfection patterns.

A

IgE antibodies against schisto is a real correlate.

77
Q

Which is the antibody that works against IgE and describes the relationship between the two and how this changes with age?

A

IgG4. This is often generated against the same epitopes as IgE and so may competitively inhibit the effect/ block IgE. IgG4 peaks in children and drops off around age 15.
Increase in IgE and drop in IgG4 aginst the same (schisto) antigens.

This also correlates with an increase in IL5 responses which promote eosinophil production and activation.

resistance correlates with ↑ IgE and ↓ IgG4

78
Q

How are skin stage schistosomula killed?

A

IgE and eosinophils. IgG4 blocks this killing. Eosinophils attach to schistosomulas opsonised by IgE.The degranulation products (major basic protein, eosinophil peroxidase, eosinophil cationic protein) of eosinophils kill the schistosomulas.

This in vitro evidence however has not been elucidated in vivo.

79
Q

How is schisto treated?

A

Community wide treatment with PZQ.

80
Q

How has schisto evolved to evade the immune response?

A

1) Tegument adaptation: trilaminate plasma membrane in cercariae, becomes heptalaminate in penetrating schistosomula in skin –> membrane bodies under the tegument produce more tegument: anything that binds to the surface is shed off quickly as surface turnover is high.
2) Antigenic complement effects: are susceptible to complement lysis so express inhibitory complement factors e.g. SCIP1 which inhibits the membrane attack complex forming. Steal anti-complement factors from the host (e.g. delay accelerating factor) prevents compliment activation on adult surface.
3) Reduced surface antigenicity: tegument turnover= reduced antigenicity. Incorporate host molecules to produce a host antigen disguise (e.g. blood group glycolipids, MHC proteins, fibronectin)

81
Q

Which are the three less common schistos? What environments do they like?

A

Japonicum, mekongi and Intercalatum. Turbid water environments.

82
Q

Why does schisto provide such high DALYs?

A
  • Builds up over time
  • Less likely to be treated
  • Living with background levels of anaemia etc.
83
Q

Wy are children often targeted by control?

A
  • More children infected (some resistance in adults)
  • Higher levels of egg shedding in children
  • Children more quickly reinfected as have less protective immunity (adults may have: thicker skin, innate resistance?)
84
Q

How much (what percentage) if variation in innate immunity is attributed to host genetic factors?

A

27%.

85
Q

What is one of the environmental predictors for schisto? How may this factor inform surveying/ surveillance?

A

Rainfall- increased rainfall may increase infection. We may want to survey these areas more and/ or could apply this to predict where else may be infected i.e. prediction mapping.

86
Q

Is the distribution of schisto widespread?

A

It is more focal. Differs between schools, certain bodies of water etc. This means that the subnational level is better than the district level due to this focality.

87
Q

How can we survey to know who has schisto and maximise the efficiency of these surveys?

A

Can give surveys to headteachers etc who can quickly and easily gather data.

88
Q

What may be the cause of diagnosing as low density of infection post treatment?

A

Lower sensitivity of diagnosis at low intensity/ low density may not pick up the infection if it is there.

89
Q

What does the urine dipstick test test for?

A

Circulating cathodic antigen.

Parasitology and entomology (26 decks)

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