From encounter to disease - Parasitology and Mycology

Question 1

Lifespan of Schistosomes

Answer 1

~15 years

Question 2

Epidemiological characteristics of schistosomiasis (3)

Answer 2

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

Question 3

Which species are infective to humans?

Answer 3

• S. Mansoni
• S. Japonicus
• S. Mekongi
• S. Intercalatum
• S. haematobium

Question 4

Describe the lifecycle of Schistosoma mansion

Answer 4

• 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

Question 5

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

Answer 5

Depends on where particle snails are present (intermediate host)

Question 6

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

Answer 6

False. Cercariae are produced by the snail

Question 7

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

Answer 7

Chemotaxis

Question 8

What is needed for cercariae to penetrate the skin?

Answer 8

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

Question 9

Why are the number of Schistosoma high

Answer 9

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

Question 10

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

Answer 10

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

How can you describe the movement of the worms?

Answer 13

Walking up and down the blood vessel system

Question 14

Blooth clotting - thrombotic events

Answer 14

Turbulence

Question 15

Pathogenesis of Schistosomiasis is really caused by…

Answer 15

Eggs produced by adult worms

Question 16

How do schistosomiasis eggs cause pathology?

Answer 16

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

Question 17

When do you treat schistosomiasis and why?

Answer 17

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

Question 18

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

Answer 18

Th2

Question 19

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

Answer 19

Eosinophils

Question 20

What are the major immune reactions against helminths?

Answer 20

• Eosinophil and mast cell activation
• Alternative macrophage activation

Question 21

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

Answer 21

• Th2 reaction
• Cytokines IL-4, IL-5, IL-13

Question 22

Describe the immune response to invasive helminths

Answer 22

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

Question 23

What does the helminth directed Th2 response lead to?

Answer 23

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

Question 24

How is a chronic schistosomiasis infection established?

Answer 24

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

Question 25

How can egg excretion factors induce a Th2 response?

Answer 25

25:25

Question 26

Differences/Similarities Helminth/Allergy

Answer 26

- Allergy: high-income settings - Helminth: low- income settings

Question 27

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

Answer 27

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

Question 28

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

Question 29

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

Answer 29

- 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

Question 30

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

Answer 30

The eggshell is cross-linked

Question 31

Do thrombocytes bind to eggs or adults?

Answer 31

Eggs, NOT adults

Question 32

Why do thrombocytes bind to eggs and not adults?

Answer 32

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

Question 33

Why do adult schistosomes don't cause thrombosis?

Answer 33

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

Question 34

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

Answer 34

Outersurface structure called the tegument

Question 35

What does this tegument consist of?

Answer 35

- Syncytium (continuous layer of fused cells) - Covered by a double membrane

Question 36

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

Answer 36

- Prevents pore forming by the complement system - Similar structures human

Question 37

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

Answer 37

- Mainly saturated phospholipids - High content of lyse-phospholipids - Rich in unusual fatty acids

Question 38

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

Answer 38

- Tegument surface structure - Mimicry - Immune modulation by excreted factors - Anti-thrombotic activity

Question 39

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

Answer 39

- Double membrane - Turn over & sloughing

Question 40

How is mimicry obtained by schistosomes?

Answer 40

Binding of host components on surface

Question 41

What are the excreted factors that cause immune modulation?

Answer 41

- Th2: omega-1 - Treg: lysol-phospholipids

Question 42

What is the anti-thrombotic activity of schistosomes?

Answer 42

Inhibition of platelet activation

Question 46

How can fungi be found?

Answer 46

Yeast or multicellular molds

Question 47

welke zorgen voor disease + percentage

Answer 47

- Mucormycota - Ascomycota - Basidiomycota

Question 48

Welke drugs hebben we

Answer 48

Echinocandins Amphotericin

Question 49

What is microbial resistance?

Answer 49

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

Question 50

How can microbial resistance be caused?

Answer 50

- Intrinsic or natural resistance, no previous drug exposure - Acquired resistance

Question 51

What is clinical resistance??

Answer 51

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

Question 52

What can be the causes of clinical resistance?

Answer 52

- Site of infection - Presence of catheters - Host immune status - Host mutations

Question 53

What is special about fungal acquired resistance?

Answer 53

Resistance can also come from the environment

Question 54

Polyenes - mode of action (7:20)

Answer 54

Polyenes act on the fungal membrane

Question 55

What can cause acquired resistance against polyenes? (3)

Answer 55

- Reduced amounts of ergosterol in cell membrane - Alteration of fungal cell membrane - Alteration of the fungal cell wall

Question 56

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

Answer 56

Inhibit the biosynthesis of ergosterol, the prinicipal sterol in fungal cell membranes Erg3 instead of Erg11

Question 57

Azoles act on...?

Answer 57

Erg11

Question 58

Name three kinds of azoles

Answer 58

- Imidazole - Triazole - Tetrazole

Question 59

Examples of Imidazoles (2) - 2 nitrogen

Answer 59

- Ketaconazole - Fluconazole

Question 60

Name examples of triazoles (3) - 3 nitrogen

Answer 60

- Voriconazole - Itraconazole - Posaconazole

Question 61

Name an example of tetrazole - 4 nitrogen

Answer 61

Oteseconazole

Question 62

What can cause acquired resistance against azoles? (3)

Answer 62

- 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

Question 63

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

Answer 63

Genetic modification of the target Erg11p (lanosterol 14a-methylase) 13:40

Question 64

How is an increased target copy number acquired?

Answer 64

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

Question 65

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

Answer 65

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

Question 66

Describe aneuploidy

Question 67

Target cannot be reached: drug efflux transporters

Answer 67

Increase of efflux transporters

Question 68

Categories of drug efflux transporters and their substrates

Answer 68

Cdr --> miconazole Mdr --> kanamycin

Question 69

Overexpression of Cdr1 and Cdr2 is due to

Answer 69

gain of function mutations in transcription factor TAC1.

Question 70

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

Answer 70

- Aneuploidy - GOF mutations R688Q and R673L

Question 71

Overexpression of Mdr1 is due to ...

Answer 71

Gain of function mutations in zinc cluster transcription factor MRR1.

Question 72

Modification of other pathway elements (seldom)

Answer 72

Inactivation of ERG3 suppresses toxicity and subsequent normal growth

Question 73

Biofilms

Question 74

Echinocandins mode-of-action

Question 75

Structure: Difference echinocandins and triterpenoids

Question 76

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

Answer 76

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

Question 77

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

Answer 77

- Stress pathways - Generate tolerate cells

Question 78

Echinocandins

Answer 78

No3 speelt geen rol

Question 79

Mutation hot spots in the fungus when using echinocandins

Answer 79

Fkst1 and Fks2 --> especially for C. albicans

Question 80

What is the MIC?

Answer 80

Minimum inhibitory concentration?

Question 81

Why do we have so little anti-fungal agents?

Answer 81

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.