Fungal Pathogens II Flashcards
Damage from disease can occur in 2 ways
- Direct damage from microorganism (e.g. not enough host response)
- Damage from host immune over-reaction
Damage to the host will have a
Disease threshold
Candida infection can cause both
Direct damage (systemic infection) Host overreaction (cutaneous infection)
Identification of virulence factors
Reverse genetics - candidate gene approach (most common) ‘is this gene important in virulence?’
Forward genetics - genome wide approach
Confirmation of virulence factors
Koch’s molecular postulates
- Disrupt target gene to create mutant strain
- Demonstrate attenuated virulence of mutant
- Reintroduce gene to restore virulence
The status of the host is very important in
Candida infection
Stages of candida infection
- Adhesion and colonisation
- Epithelial penetration
- Vascular dissemination
- Endothelial colonisation and penetration
C albicans virulence is
Multi factorial
Candida virulence factors
- Adhesion to host surfaces
- Invasion of epithelial layers
- Penetration beyond epithelia
- Obtaining nutrients
- Opposing host defences
Host defences
- Flushing mechanisms
- Molecular recognition
- Phagocytosis and killing
- Immune response
Characteristics of candida
- Diploid (8 chromosomes)
- Largely asexual
- Polymorphic
- CUG codon
- Causes candidosis
C albicans polymorphisms
- Yeast
- Pseudohyphae
- Hyphae
- Opaque
- Chlamydospore
What causes hyphal growth
High temps above 35 Neutral pH 6.5 High pCO2 low pO2 N/C starvation Matrix embedded growth
What causes yeast growth
Low temps below 35
Acidic pH
Nutritious environment NH4+ ions
What also plays a role in morphogensis between yeast and hyphae?
Quorum sensing
Quorum sensing tells candida in high cell densities
To grow as a yeast
Quorum sensing tells candida in low cell densities
To grow as hyphae
Virulence of hyphal morphology
Tissue penetration
Virulence of yeast morphology
Vascular dissemination
The ability to switch morphologies in candida is key to its
Virulence
Yeast or hyphae morphology locked mutants
Show attenuated virulence
Damage to the host is mainly through which form of candida?
Hyphal
Hyphae have both direct and indirect roles in
Virulence
Direct roles of hyphae in virulence
Invasion
Thigmotropism
Escape from phagocytes
Indirect roles of hyphae in virulence
Through genes co regulated with morphogenesis (eg toxins)
Candida lysin is a toxin that is only produced by
Hyphal cells
What toxin does hyphal candida produce
Candida lysin
When candida yeast cells are engulfed by a phagocyte
They switch to hyphal morphology and erupt from the phagocyte
Candida is very ‘sticky’ and can adhere to
Epithelium/Endothelium
Medical devices
Biofilms
Bacteria
How does candida adhere to surfaces?
Cell surface Manno proteins
glycosylated
Which gene family is used in candida adherence?
ALS family
Agglutinin like sequence family of cell wall proteins
Als3
ALS protein
Especially important in adherence
Candida invasion is done through 2 routes
- Induced endocytosis
2. Active penetration
Induced endocytosis
Fungal ‘invasin’ interacts with cell surface proteins
Fungus is engulfed - ‘zipper like’
Active penetration
Directly through or inbetween cells
- Physical force from directional growth and turgor pressure
- Secreted hydrolytic enzymes damage host tissue
Candida biofilms are
Structured assemblies encased in an extracellular matrix
Biofilms are inherently
Resistant
To host defences and drug therapy
Stages of biofilm development
A I M D
A - ttachment
I - nitiation
M - aturation
D - ispersal
Main type of hydrolytic enzyme produced by candida
Aspartic proteinases
Candida has strategies to uptake which nutrient from the host?
Iron
Candida iron uptake methods
- Reductive pathway (rips iron out of ferritin)
- Siderophore uptake (iron carriers produced by other microbes in vicinity)
- Haemoglobin destruction (binds to Hb and and tears out the haem to access iron)
Candida can deal with the stresses of an immune response by
Switching to hyphal form
