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I&I WC1 > From encounter to disease - Parasitology and Mycology > Flashcards

From encounter to disease - Parasitology and Mycology Flashcards

This deck contains the lectures about schistosomiasis and anti-fungal resistance

1
Q

Lifespan of Schistosomes

A

~15 years

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2
Q

Epidemiological characteristics of schistosomiasis (3)

A
  • Disease in tropical and subtropical areas
  • Only 10% symptomatic
  • Caused by flatworm (trematode): Schistosoma spp
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3
Q

Which species are infective to humans?

A
  • S. Mansoni
  • S. Japonicus
  • S. Mekongi
  • S. Intercalatum
  • S. haematobium
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4
Q

Describe the lifecycle of Schistosoma mansion

A
  • Eggs via stool/urine
  • Eggs come in contact with fresh water
  • Larvae (miracidia) hatches from egg
  • Replication in intermediate host (fresh water snails)
  • Cercariae release from snail
  • Skin penetration of definite host
  • Migration to mesenteric vains and pairing of male and female
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5
Q

Geography: Why is schistose weirdly/patchy distributed among the world?

A

Depends on where particle snails are present (intermediate host)

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6
Q

True or False: “Cercariae are produced by the parasite.”

A

False. Cercariae are produced by the snail

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7
Q

How can these cercariae find their way to the skin to penetrate?

A

Chemotaxis

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8
Q

What is needed for cercariae to penetrate the skin?

A
  • Head structure with glands that produce proteases to degrade skin proteins
  • Mechanical force of the tail movement
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9
Q

Why are the number of Schistosoma high

A

Fresh water is schaars, so lots of people visit these waters become infect

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10
Q

What happens to the head structure after penetrating the skin? Why?

A

They shed of their head structure –> because it’s an antigenic structure

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11
Q
A

Acquiring of a new head structure that is less/not antigenic

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12
Q

Which distinction can be made based on the colour of the worms?

A

White: males
Black: female –> digest erythrocytes, but cannot digest heem
Grey: -

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13
Q

How can you describe the movement of the worms?

A

Walking up and down the blood vessel system

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14
Q

Blooth clotting - thrombotic events

A

Turbulence

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15
Q

Pathogenesis of Schistosomiasis is really caused by…

A

Eggs produced by adult worms

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16
Q

How do schistosomiasis eggs cause pathology?

A

Trapped eggs contains eggshell which is cross-lit

Eggshell –> cross linked –> proteases cannot degrade it –> stays immunogenic –> ongoing immune response –> granuloma formation –> loss of tissue function

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17
Q

When do you treat schistosomiasis and why?

A

Before symptoms occur. Killing adult worms does not really do anything if their eggs have already caused symptoms

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18
Q

Which kind of Th response is the classical response against helminths?

A

Th2

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19
Q

What are the principal target cells during the host immune response?

A

Eosinophils

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20
Q

What are the major immune reactions against helminths?

A
  • Eosinophil and mast cell activation
  • Alternative macrophage activation
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21
Q

What kind of immune response is elicited against helminth infections and which cytokines are involved?

A
  • Th2 reaction
  • Cytokines IL-4, IL-5, IL-13
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22
Q

Describe the immune response to invasive helminths

A
  • Eosinophils expand
  • Bind and recognize helminth structures
  • Granulate with anti-helminth components
  • Induce antibodies (IgE)
  • Crosslinking mast cells
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23
Q

What does the helminth directed Th2 response lead to?

A

Mucus synthesis leading to an increased barrier via which helminths can penetrate

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24
Q

How is a chronic schistosomiasis infection established?

A

Intensity of Th2 response is reduced, induction of regulatory T cell response

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25
Q

How can egg excretion factors induce a Th2 response?

A

25:25

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26
Q

Differences/Similarities Helminth/Allergy

A
  • Allergy: high-income settings
  • Helminth: low- income settings
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27
Q

What does the hygiene hypothesis mean with respect to helminth infections?

A

Helminth infection induces Th2 response, but at the same time it suppresses it by Treg response –> Negative-feedback mechanism in place

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28
Q

Most of the blood vessel is occupied by the adult worm-pair causing tremendous turbulence. Why does this not cause thrombosis?

A
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29
Q

What happens after when a thrombocyte binds to a schistosome egg? (6)

A
  • Connect eggs to the underlying surface
  • Endothelial cells overgrow it after binding
  • Eggs excrete protein factors and attract leukocytes
  • Leukocytes can’t phagocytose the egg
  • Only degranulation and release of proteases
  • Eggshell can’t be degraded –> your own external matrix is dissolved
  • Egg has some room to move –> can go through tissue
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30
Q

Why can’t the egg be degraded by the leukocyte?

A

The eggshell is cross-linked

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31
Q

Do thrombocytes bind to eggs or adults?

A

Eggs, NOT adults

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32
Q

Why do thrombocytes bind to eggs and not adults?

A

Eggs and thrombocytes have a strong adhesion since they need to stay stuck in the blood vessel to migrate to the tissue to get excreted

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33
Q

Why do adult schistosomes don’t cause thrombosis?

A

Adults don’t cause primary clotting because they don’t attract and bind thrombocytes + adults suppress secondary clotting cascade

34
Q

What is special about the outer-surface of adult schistosomes?

A

Outersurface structure called the tegument

35
Q

What does this tegument consist of?

A
  • Syncytium (continuous layer of fused cells)
  • Covered by a double membrane
36
Q

What are the protective functions of the double membrane from the tegument? (2)

A
  • Prevents pore forming by the complement system
  • Similar structures human
37
Q

Describe the lipid composition of tegumental membranes of schistosomiasis (3)

A
  • Mainly saturated phospholipids
  • High content of lyse-phospholipids
  • Rich in unusual fatty acids
38
Q

How do schistosomes survive for years in the human blood vessel?

A
  • Tegument surface structure
  • Mimicry
  • Immune modulation by excreted factors
  • Anti-thrombotic activity
39
Q

Which two factors of the tegument surface structure cause schistosomes to survive for years in the human blood vessel?

A
  • Double membrane
  • Turn over & sloughing
40
Q

How is mimicry obtained by schistosomes?

A

Binding of host components on surface

41
Q

What are the excreted factors that cause immune modulation?

A
  • Th2: omega-1
  • Treg: lysol-phospholipids
42
Q

What is the anti-thrombotic activity of schistosomes?

A

Inhibition of platelet activation

43
Q
A
44
Q
A
45
Q
A
46
Q

How can fungi be found?

A

Yeast or multicellular molds

47
Q

welke zorgen voor disease + percentage

A
  • Mucormycota
  • Ascomycota
  • Basidiomycota
48
Q

Welke drugs hebben we

A

Echinocandins
Amphotericin

49
Q

What is microbial resistance?

A

Decreased susceptibility of a fungal strain to anantifungal agent in standardized in vitro susceptibility testing

50
Q

How can microbial resistance be caused?

A
  • Intrinsic or natural resistance, no previous drug exposure
  • Acquired resistance
51
Q

What is clinical resistance??

A

Therapeutic failure: a patient responds inadequately to an antifungal drug following administration of a standard dose.

52
Q

What can be the causes of clinical resistance?

A
  • Site of infection
  • Presence of catheters
  • Host immune status
  • Host mutations
53
Q

What is special about fungal acquired resistance?

A

Resistance can also come from the environment

54
Q

Polyenes - mode of action (7:20)

A

Polyenes act on the fungal membrane

55
Q

What can cause acquired resistance against polyenes? (3)

A
  • Reduced amounts of ergosterol in cell
    membrane
  • Alteration of fungal cell membrane
  • Alteration of the fungal cell wall
56
Q

What is the mode-of-action of azoles and allylamines? (10:30)

A

Inhibit the biosynthesis of ergosterol, the prinicipal sterol in fungal cell membranes

Erg3 instead of Erg11

57
Q

Azoles act on…?

A

Erg11

58
Q

Name three kinds of azoles

A
  • Imidazole
  • Triazole
  • Tetrazole
59
Q

Examples of Imidazoles (2) - 2 nitrogen

A
  • Ketaconazole
  • Fluconazole
60
Q

Name examples of triazoles (3) - 3 nitrogen

A
  • Voriconazole
  • Itraconazole
  • Posaconazole
61
Q

Name an example of tetrazole - 4 nitrogen

A

Oteseconazole

62
Q

What can cause acquired resistance against azoles? (3)

A
  • Target is changed: reduced drug-target interaction
    Increase in target copy number
    3.Reduction of intracellular drug concentrations mediated via drug efflux transporters and reduced uptake
    4.Modification of other ergosterol biosynthesis pathway elements
    5. Biofilms and persistor cells
63
Q

How is reduced drug-target interaction (azoles) acquired?

A

Genetic modification of the target Erg11p (lanosterol 14a-methylase)

13:40

64
Q

How is an increased target copy number acquired?

A

Multiple copies of Erg11p due to mutations in the promotor gene UPC2

65
Q

What happens to the dose of an azole drug if the fungus has an increased target copy number?

A

You need a higher concentration of the drug to have the same effect

66
Q

Describe aneuploidy

A
67
Q

Target cannot be reached: drug efflux transporters

A

Increase of efflux transporters

68
Q

Categories of drug efflux transporters and their substrates

A

Cdr –> miconazole
Mdr –> kanamycin

69
Q

Overexpression of Cdr1 and Cdr2 is due to

A

gain of function mutations in transcription factor TAC1.

70
Q

How can these gain of function mutations in Cdr1 and Cdr2 occur?

A
  • Aneuploidy
  • GOF mutations R688Q and R673L
71
Q

Overexpression of Mdr1 is due to …

A

Gain of function mutations in zinc cluster transcription factor MRR1.

72
Q

Modification of other pathway elements (seldom)

A

Inactivation of ERG3 suppresses toxicity and subsequent normal growth

73
Q

Biofilms

A
74
Q

Echinocandins mode-of-action

A
75
Q

Structure: Difference echinocandins and triterpenoids

A
76
Q

Describe the paradoxal effect of the echinocandins (24:30)

A

Low concentration of anti-fungal agents –> you don’t see any effect of growth, above MIC cell kill

77
Q

What happens in the adaptation zone? (duidelijk plaatje pagina 22)

A
  • Stress pathways
  • Generate tolerate cells
78
Q

Echinocandins

A

No3 speelt geen rol

79
Q

Mutation hot spots in the fungus when using echinocandins

A

Fkst1 and Fks2 –> especially for C. albicans

80
Q

What is the MIC?

A

Minimum inhibitory concentration?

81
Q

Why do we have so little anti-fungal agents?

A

Fungal cells resemble our own cells too much. It is really to hard to find drugs that are specific enough so that they don’t attack our own cells.

I&I WC1 (25 decks)

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