22 Fungal Pathogens Flashcards
where are superficial fungal infections
skin and mucosa
who is at risk to getting fungal infections
Appears in apparently healthy individuals (so all can be at risk e.g. athlete’s foot)
- Genetic predisposition assumed
what causes thrush
Candida albicans
what is Candida albicans like
commensal – living inside the body participating in the food that you take up but does not cause disease – however
what are superficial fungal infections like
not life threatening
what are invasive fungal infections like
life threatening
will penetrate into the tissues and may disseminate within the body and affect different organs
(require predisposition)
examples of those that are more vunerable to infection
- HIV infection - AIDS
- Surgery
- Open wounds (burn wounds)
- Immunodeficiency disorders
what is the major risk factors for acquisition of invasive fungal infections
Defects in innate immune response are
what is important with fungal infection treatment
progression of disease is very fast – requires early diagnosis and early start of therapy
why are antibodies not effective in fungal infections
AB formation takes a long time (too late for fungal infection)
what are the key cells involved in innate immunity in invasive fungal infections
- Macrophages/Monocytes
- Neutrophils
- Dendritic cells
- T-cells
- Complement
what is the role of neutrophils in innate immunity
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)
what is the role of dendritic cells in innate immunity
professional phagocytic cells, main cells that migrate to draining lymph nodes and present antigens to T cells
what is the role of T cells in innate immunity
orchestrate the immune response by stimulating further immune response or by tuning down the immune response
what is the role of complement in innate immunity
(opsonisation) fungal pathogens to be recognised by immune cells and taken up
what do receptors recognise
fungal cell wall components
what is the cell wall mainly made of
sugar polymers
how are closed form glucose molecules made
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
what is in the standard core components of fungal the cell wall
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)
what is used in species-dependent presentation of other components
PAMPS
which PRRs are used when
many different receptors that are able to identify specific PAMPS
what is CLR
C-type lectin receptors
what is NLRs
NOD-like receptors
what is TLRs
toll like receptors
what cells can interact with the different fungal elements
macrophage, neutrophil, dendritic cells, NK cells
macrophage interaction with immune cells
Macrophages can feed info to T cells as they can present antigens and are stimulated in response
what do the receptors on macrophage, neutrophil, dendritic cells, NK cells cause
Number of different receptors on these cells (not as many on NK) elicit a specific response
what are Macrophages and Monocytes
Professional phagocytes
what do macrophages and monocytes recognise
fungi using PRR
what do macrophages and monocytes make
acidic phagolysosomes
what do macrophages and monocytes cause
Orchestrate immune response by cytokines
what does RAB in monocytes and macrophages cause
GTPases for fusion with lysosomes
what happens in macrophage escape
- Intracellular proliferation
- Elongating hyphae
what is the specific macrophages in the lungs
alveolar macrophages
what do the alveolar macrophages do
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
what do dendritic cells with anti-fungal PRRs recognise and effect
Th1/17 (INF/IL17)
adaptive immune response with activation of innate effector cells
where are neutrophils
Recruited from blood to site of infection
what do neutrophils do
- Phagocytose bacteria and fungi
- Release toxic metabolites and peptides
what do neutrophils produce
- Produce reactive oxygen species
- Produce extracellular traps
what is NET
Neutrophil Extracellular Trap
when is a NET made
when neutrophil dies
what occurs in NET formation
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
what can neutrophils attack
large structures
how do fungi avoid phagocytosis
increase in size
what is the importance of T cells
Main contributors in fungal infections: Regulatory T-cells, cytotoxic T-cells
what are the main sub-types of T cells
- CD4+CD8- T cells > Th1 > Th2 > Th17 - CD4-CD8+ killer T cells
what is the Th1 response
Stimulation of macrophages
what is the Th2 response
B cells, Eosinophils, Basophils –> Chronic disease
what is the Th17 response
Recruitment and activation of neutrophils
what is important in complement pathway
C3-dependent alternative pathway
rely on opsonisation to increase recognition by phagocytes
what is the problem with antifungal treatment options
- 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
what are the three major classes of antifungals
- Polyene macrolides
- Echinocandins
- Azoles
what are examples of major targets of antifungals
beta-1,3 glucan
beta-1,3 glucan synthase
ergosterol
ergosterol synthesis pathway
what is the difference in cholesterol and ergosterol
Cholesterol in humans
Ergosterol in fungi
what does cholesterol and ergosterol do
- Regulate the fluidity of membranes
- Essential molecule in eukaryotic cell membranes
what is the action of polyene macrolides
- Bind to ergosterol in the cell membrane
- Higher affinity to ergosterol than cholesterol
what is the mechanism of polyene macrolides
mechanism 1 - Binding Pore formation Permeabilisation
mechanism 2 - Forms ion leakage channels (K+, Na+, Ca2+)
what is the action of azoles
- bind to inhibit demethylation
- Block ergosterol biosynthesis
what is the affect of azoles
> Accumulation of (toxic) intermediates
> Alteration of membrane fluidity
what is the action of echinocandins
- 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)
