22 Fungal Pathogens

Question 1

where are superficial fungal infections

Answer 1

skin and mucosa

Question 2

who is at risk to getting fungal infections

Answer 2

Appears in apparently healthy individuals (so all can be at risk e.g. athlete’s foot)
- Genetic predisposition assumed

Question 3

what causes thrush

Answer 3

Candida albicans

Question 4

what is Candida albicans like

Answer 4

commensal – living inside the body participating in the food that you take up but does not cause disease – however

Question 5

what are superficial fungal infections like

Answer 5

not life threatening

Question 6

what are invasive fungal infections like

Answer 6

life threatening
will penetrate into the tissues and may disseminate within the body and affect different organs
(require predisposition)

Question 7

examples of those that are more vunerable to infection

Answer 7

• HIV infection - AIDS
• Surgery
• Open wounds (burn wounds)
• Immunodeficiency disorders

Question 8

what is the major risk factors for acquisition of invasive fungal infections

Answer 8

Defects in innate immune response are

Question 9

what is important with fungal infection treatment

Answer 9

progression of disease is very fast – requires early diagnosis and early start of therapy

Question 10

why are antibodies not effective in fungal infections

Answer 10

AB formation takes a long time (too late for fungal infection)

Question 11

what are the key cells involved in innate immunity in invasive fungal infections

Answer 11

• Macrophages/Monocytes
• Neutrophils
• Dendritic cells
• T-cells
• Complement

Question 12

what is the role of neutrophils in innate immunity

Answer 12

very effective, but will cause tissue damage if always recruited (need to be recruited to the site of infection – they’re made in bone marrow and circulate in the blood)

Question 13

what is the role of dendritic cells in innate immunity

Answer 13

professional phagocytic cells, main cells that migrate to draining lymph nodes and present antigens to T cells

Question 14

what is the role of T cells in innate immunity

Answer 14

orchestrate the immune response by stimulating further immune response or by tuning down the immune response

Question 15

what is the role of complement in innate immunity

Answer 15

(opsonisation) fungal pathogens to be recognised by immune cells and taken up

Question 16

what do receptors recognise

Answer 16

fungal cell wall components

Question 17

what is the cell wall mainly made of

Answer 17

sugar polymers

Question 18

how are closed form glucose molecules made

Answer 18

OH important in the polymer formation, by connecting to another glucose unit
Closure of the glucose ring can lead to alpha (point down) or beta (point up) glucose
OH on 1 attaches to glucose on 6

Question 19

what is in the standard core components of fungal the cell wall

Answer 19

top layer as protein rich in mannose sugar
glucans (beta1,3 glucan is the dominating) – formed by beta 1,3 glucan synthase
inner layer above cell membrane – chitin layer (polymer)

Question 20

what is used in species-dependent presentation of other components

Answer 20

PAMPS

Question 21

which PRRs are used when

Answer 21

many different receptors that are able to identify specific PAMPS

Question 22

what is CLR

Answer 22

C-type lectin receptors

Question 23

what is NLRs

Answer 23

NOD-like receptors

Question 24

what is TLRs

Answer 24

toll like receptors

Question 25

what cells can interact with the different fungal elements

Answer 25

macrophage, neutrophil, dendritic cells, NK cells

Question 26

macrophage interaction with immune cells

Answer 26

Macrophages can feed info to T cells as they can present antigens and are stimulated in response

Question 27

what do the receptors on macrophage, neutrophil, dendritic cells, NK cells cause

Answer 27

Number of different receptors on these cells (not as many on NK) elicit a specific response

Question 28

what are Macrophages and Monocytes

Answer 28

Professional phagocytes

Question 29

what do macrophages and monocytes recognise

Answer 29

fungi using PRR

Question 30

what do macrophages and monocytes make

Answer 30

acidic phagolysosomes

Question 31

what do macrophages and monocytes cause

Answer 31

Orchestrate immune response by cytokines

Question 32

what does RAB in monocytes and macrophages cause

Answer 32

GTPases for fusion with lysosomes

Question 33

what happens in macrophage escape

Answer 33

- Intracellular proliferation | - Elongating hyphae

Question 34

what is the specific macrophages in the lungs

Answer 34

alveolar macrophages

Question 35

what do the alveolar macrophages do

Answer 35

policed to recognise anything foreign entering the lungs (may or may not be pathogenic) if high concentration of pathogens recruit other cells to aid clearing

Question 36

what do dendritic cells with anti-fungal PRRs recognise and effect

Answer 36

Th1/17 (INF/IL17) | adaptive immune response with activation of innate effector cells

Question 37

where are neutrophils

Answer 37

Recruited from blood to site of infection

Question 38

what do neutrophils do

Answer 38

- Phagocytose bacteria and fungi | - Release toxic metabolites and peptides

Question 39

what do neutrophils produce

Answer 39

- Produce reactive oxygen species | - Produce extracellular traps

Question 40

what is NET

Answer 40

Neutrophil Extracellular Trap

Question 41

when is a NET made

Answer 41

when neutrophil dies

Question 42

what occurs in NET formation

Answer 42

Leads to modification of macrophage to cause chromatin condensation DNA strongly packed in nucleus – starts to unpack (gets larger) histones (sticky molecules) stay on the membrane Will have granules with toxic metabolites

Question 43

what can neutrophils attack

Answer 43

large structures

Question 44

how do fungi avoid phagocytosis

Answer 44

increase in size

Question 45

what is the importance of T cells

Answer 45

Main contributors in fungal infections: Regulatory T-cells, cytotoxic T-cells

Question 46

what are the main sub-types of T cells

Answer 46

``` - CD4+CD8- T cells > Th1 > Th2 > Th17 - CD4-CD8+ killer T cells ```

Question 47

what is the Th1 response

Answer 47

Stimulation of macrophages

Question 48

what is the Th2 response

Answer 48

B cells, Eosinophils, Basophils --> Chronic disease

Question 49

what is the Th17 response

Answer 49

Recruitment and activation of neutrophils

Question 50

what is important in complement pathway

Answer 50

C3-dependent alternative pathway | rely on opsonisation to increase recognition by phagocytes

Question 51

what is the problem with antifungal treatment options

Answer 51

- Fungi and human host are both eukaryotes (want to taret the fungal eukaryotes not the human eukaryotes – so only target fungus pathogen, need to find differences) - Antifungal drug should specifically target the fungal pathogen - Targets need to consist of molecules essential for fungal survival

Question 52

what are the three major classes of antifungals

Answer 52

- Polyene macrolides - Echinocandins - Azoles

Question 53

what are examples of major targets of antifungals

Answer 53

beta-1,3 glucan beta-1,3 glucan synthase ergosterol ergosterol synthesis pathway

Question 54

what is the difference in cholesterol and ergosterol

Answer 54

Cholesterol in humans | Ergosterol in fungi

Question 55

what does cholesterol and ergosterol do

Answer 55

- Regulate the fluidity of membranes | - Essential molecule in eukaryotic cell membranes

Question 56

what is the action of polyene macrolides

Answer 56

- Bind to ergosterol in the cell membrane | - Higher affinity to ergosterol than cholesterol

Question 57

what is the mechanism of polyene macrolides

Answer 57

mechanism 1 - Binding Pore formation Permeabilisation | mechanism 2 - Forms ion leakage channels (K+, Na+, Ca2+)

Question 58

what is the action of azoles

Answer 58

- bind to inhibit demethylation | - Block ergosterol biosynthesis

Question 59

what is the affect of azoles

Answer 59

> Accumulation of (toxic) intermediates | > Alteration of membrane fluidity

Question 60

what is the action of echinocandins

Answer 60

- cell wall depleted with beta 1,3 glucan due to inhibition of β-1,3-glucan synthase - weakening of fungal cell wall (loserigidity of cell wall)