From encounter to disease - Parasitology and Mycology Flashcards
This deck contains the lectures about schistosomiasis and anti-fungal resistance
Lifespan of Schistosomes
~15 years
Epidemiological characteristics of schistosomiasis (3)
- Disease in tropical and subtropical areas
- Only 10% symptomatic
- Caused by flatworm (trematode): Schistosoma spp
Which species are infective to humans?
- S. Mansoni
- S. Japonicus
- S. Mekongi
- S. Intercalatum
- S. haematobium
Describe the lifecycle of Schistosoma mansion
- 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
Geography: Why is schistose weirdly/patchy distributed among the world?
Depends on where particle snails are present (intermediate host)
True or False: “Cercariae are produced by the parasite.”
False. Cercariae are produced by the snail
How can these cercariae find their way to the skin to penetrate?
Chemotaxis
What is needed for cercariae to penetrate the skin?
- Head structure with glands that produce proteases to degrade skin proteins
- Mechanical force of the tail movement
Why are the number of Schistosoma high
Fresh water is schaars, so lots of people visit these waters become infect
What happens to the head structure after penetrating the skin? Why?
They shed of their head structure –> because it’s an antigenic structure
Acquiring of a new head structure that is less/not antigenic
Which distinction can be made based on the colour of the worms?
White: males
Black: female –> digest erythrocytes, but cannot digest heem
Grey: -
How can you describe the movement of the worms?
Walking up and down the blood vessel system
Blooth clotting - thrombotic events
Turbulence
Pathogenesis of Schistosomiasis is really caused by…
Eggs produced by adult worms
How do schistosomiasis eggs cause pathology?
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
When do you treat schistosomiasis and why?
Before symptoms occur. Killing adult worms does not really do anything if their eggs have already caused symptoms
Which kind of Th response is the classical response against helminths?
Th2
What are the principal target cells during the host immune response?
Eosinophils
What are the major immune reactions against helminths?
- Eosinophil and mast cell activation
- Alternative macrophage activation
What kind of immune response is elicited against helminth infections and which cytokines are involved?
- Th2 reaction
- Cytokines IL-4, IL-5, IL-13
Describe the immune response to invasive helminths
- Eosinophils expand
- Bind and recognize helminth structures
- Granulate with anti-helminth components
- Induce antibodies (IgE)
- Crosslinking mast cells
What does the helminth directed Th2 response lead to?
Mucus synthesis leading to an increased barrier via which helminths can penetrate
How is a chronic schistosomiasis infection established?
Intensity of Th2 response is reduced, induction of regulatory T cell response
How can egg excretion factors induce a Th2 response?
25:25
Differences/Similarities Helminth/Allergy
- Allergy: high-income settings
- Helminth: low- income settings
What does the hygiene hypothesis mean with respect to helminth infections?
Helminth infection induces Th2 response, but at the same time it suppresses it by Treg response –> Negative-feedback mechanism in place
Most of the blood vessel is occupied by the adult worm-pair causing tremendous turbulence. Why does this not cause thrombosis?
What happens after when a thrombocyte binds to a schistosome egg? (6)
- 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
Why can’t the egg be degraded by the leukocyte?
The eggshell is cross-linked
Do thrombocytes bind to eggs or adults?
Eggs, NOT adults
Why do thrombocytes bind to eggs and not adults?
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
Why do adult schistosomes don’t cause thrombosis?
Adults don’t cause primary clotting because they don’t attract and bind thrombocytes + adults suppress secondary clotting cascade
What is special about the outer-surface of adult schistosomes?
Outersurface structure called the tegument
What does this tegument consist of?
- Syncytium (continuous layer of fused cells)
- Covered by a double membrane
What are the protective functions of the double membrane from the tegument? (2)
- Prevents pore forming by the complement system
- Similar structures human
Describe the lipid composition of tegumental membranes of schistosomiasis (3)
- Mainly saturated phospholipids
- High content of lyse-phospholipids
- Rich in unusual fatty acids
How do schistosomes survive for years in the human blood vessel?
- Tegument surface structure
- Mimicry
- Immune modulation by excreted factors
- Anti-thrombotic activity
Which two factors of the tegument surface structure cause schistosomes to survive for years in the human blood vessel?
- Double membrane
- Turn over & sloughing
How is mimicry obtained by schistosomes?
Binding of host components on surface
What are the excreted factors that cause immune modulation?
- Th2: omega-1
- Treg: lysol-phospholipids
What is the anti-thrombotic activity of schistosomes?
Inhibition of platelet activation
How can fungi be found?
Yeast or multicellular molds
welke zorgen voor disease + percentage
- Mucormycota
- Ascomycota
- Basidiomycota
Welke drugs hebben we
Echinocandins
Amphotericin
What is microbial resistance?
Decreased susceptibility of a fungal strain to anantifungal agent in standardized in vitro susceptibility testing
How can microbial resistance be caused?
- Intrinsic or natural resistance, no previous drug exposure
- Acquired resistance
What is clinical resistance??
Therapeutic failure: a patient responds inadequately to an antifungal drug following administration of a standard dose.
What can be the causes of clinical resistance?
- Site of infection
- Presence of catheters
- Host immune status
- Host mutations
What is special about fungal acquired resistance?
Resistance can also come from the environment
Polyenes - mode of action (7:20)
Polyenes act on the fungal membrane
What can cause acquired resistance against polyenes? (3)
- Reduced amounts of ergosterol in cell
membrane - Alteration of fungal cell membrane
- Alteration of the fungal cell wall
What is the mode-of-action of azoles and allylamines? (10:30)
Inhibit the biosynthesis of ergosterol, the prinicipal sterol in fungal cell membranes
Erg3 instead of Erg11
Azoles act on…?
Erg11
Name three kinds of azoles
- Imidazole
- Triazole
- Tetrazole
Examples of Imidazoles (2) - 2 nitrogen
- Ketaconazole
- Fluconazole
Name examples of triazoles (3) - 3 nitrogen
- Voriconazole
- Itraconazole
- Posaconazole
Name an example of tetrazole - 4 nitrogen
Oteseconazole
What can cause acquired resistance against azoles? (3)
- 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
How is reduced drug-target interaction (azoles) acquired?
Genetic modification of the target Erg11p (lanosterol 14a-methylase)
13:40
How is an increased target copy number acquired?
Multiple copies of Erg11p due to mutations in the promotor gene UPC2
What happens to the dose of an azole drug if the fungus has an increased target copy number?
You need a higher concentration of the drug to have the same effect
Describe aneuploidy
Target cannot be reached: drug efflux transporters
Increase of efflux transporters
Categories of drug efflux transporters and their substrates
Cdr –> miconazole
Mdr –> kanamycin
Overexpression of Cdr1 and Cdr2 is due to
gain of function mutations in transcription factor TAC1.
How can these gain of function mutations in Cdr1 and Cdr2 occur?
- Aneuploidy
- GOF mutations R688Q and R673L
Overexpression of Mdr1 is due to …
Gain of function mutations in zinc cluster transcription factor MRR1.
Modification of other pathway elements (seldom)
Inactivation of ERG3 suppresses toxicity and subsequent normal growth
Biofilms
Echinocandins mode-of-action
Structure: Difference echinocandins and triterpenoids
Describe the paradoxal effect of the echinocandins (24:30)
Low concentration of anti-fungal agents –> you don’t see any effect of growth, above MIC cell kill
What happens in the adaptation zone? (duidelijk plaatje pagina 22)
- Stress pathways
- Generate tolerate cells
Echinocandins
No3 speelt geen rol
Mutation hot spots in the fungus when using echinocandins
Fkst1 and Fks2 –> especially for C. albicans
What is the MIC?
Minimum inhibitory concentration?
Why do we have so little anti-fungal agents?
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.
