14 Fungal pathogens Flashcards
Classification of fungi (3)
Yeast
budding
Fliamentous fungi
Hyphae and mycelia
Dimorphic fungi
temperature dependent morphology (yeast vs mold)
Fungal cell wall
and PRRs
Components
Phospholipid bilayer with membrane proteins
Chitin
ß-1,3-glycan
ß-1,6-glycan
Mannan
PRRs
Mincle, TLR-4, DC-SIGN, Dectin, CR
What is LAP ?
How can LAP be inhibited ?
How is autophagy in general activated and what’s the result?
LAP
LC3 associated phagocytosis
Phagocytic cargo cell will be taken up by phagosome, then the LC3 lipidation machinery will lead to an aggregation of LC3 on the phagosome.
LC3 facilitates lysosomal fusion, leads to a rapid degradation and promotes immune silence
How can LAP be inhibited ?
e.g. ROS species can have negative influence, this LC3 negative LAPosome leads to decreased lysosomal fusion, longer cargo degradation and inflammatory responses
How is autophagy in general activated and what’s the result?
Non Starving condition like high glucose and high amino acids lead to an activation of mTORC that leads to phosphorylation of different proteins that inhibit autophagy, when starving conditions are present autophagy is active
Histoplasma capsulatum
life cycle and disease
life cycle
facultative intracellular fungus with thermal dimorphism (mold in enviroment, yeast in human)
Internalized by phagocytes
PMN and DC inhibit growth but Macrophage inhibtion of growth needs cellular activation TH1 response
Disease
pulmonary infections and systemic mycosis in immunosupressed patients -> antimycotic treatment
What are the immune responses against histoplasmna capsulatum ?
Dectin2/1 Inflammasome activation
Activation of Syk, activation of JNK and ERK leading to:
1: gene activation: pro-IL-1ß
2: Lysosome rupture activated by JNK/ERK leads to Cathepsin B activated NLRP3 Inflammasome (also activated by K+ channels) that converts pro-IL-1-ß into IL-1ß to induce proinflammatory mechanisms
Cathepsins
location
function
Pathology
location
in lysosomes, endsomes
function
activated by low pH, proteases, hydrolytic cleavage
Part of immune response, autophagy, coagulation
Pathology
Cancer, Autoimmune diseases, allergy
IL-1ß in fungal immunity
mechanism
pro-IL-1ß is activated through cleavage by caspase 1 activated by Inflammasome and is secreted in PIP2-rich plasma membrane ruffles
Caspase 1 also activated GSDMD that can facilitate secretion of IL-1ß through pores
Hijacking of metabolic pathways
example
Hijacking
Glucose converted by C. albicans to kill macrophage
Calcium sequestration inhibits assembly of lysosomal components to kill pathogen
Lactate for signal of masking of ß-glycan
Candida albicans
Pathomechanisms (8)
Pathogenicities in oral and vulvovaginal candidiasis
Adhesins
Yeast to hyphae transition
Invasins
Fungal hydrolases
Biofilm (lower part yeast, higher part hyphae)
Hsp
Extracellular alkanization
Uptake of metals
Oral
Il1ß release and NET formation by neutrophils, efficient phagocytosis
Vaginal
increased cytokine release and impaired complement binding lead to Impaired phagocytosis and NET release, low levels of IL-6
Aspergillus fumigatus
Immune activation
How to survive in enviroment?
Inhalation of airborne conidia:
3 defense cells / mechanism:
- complement system
- Alveolar macrophages
- PMN
hyphae state can be cleared, therefore fast germination rate = lower virulence
Enviroment
‘Conidiophore -> Conidium in enviroment
Rodlets to protect against dehydration, PAMP masking, conidial dispersion
Melanin for UV light and masking of PAMPs and ROS + LAP inhibition
Galactosaminogalactan for Adhesion, Masking of glycan, anti inflammatory PAMP
Biofilm
Chronic diseases as result of Aspergillus fumigatus
Immunosupression: Aspergillosis
Lung disease: Aspergilloma
Chronic lung disease
Asthma: ABPA (allergy)
Crytococcus neoformans
sexual reproduction
Niches in enviroment
Interaction with ?
Cell structures
Infection of humans
Transmission in body
sexual reproduction
bisexual mating and unisexual mating possible
bisexual via nuclear fusion of germ cells a/b and meiosis and sporulation
unisexual via diplodization, meiosis and sporulation
Niches in enviroment
soil, tree
Interaction with ?
amoebae
Cell structures
Melanin right next to Chitin
Capsule (Galacto and Glucoronoxylmannan)
Infection of humans
via inhaling spores or dried yeast
Transmission
pulmonary infection
yeast cell can differentiate into titan cell
blood stream dissemination
crossing blood brain barrier
Which immune response leads to clearence, dormany and dissemination of Crytoccoccus neoformans ?
clearence: TH1 response (IFN.gamma, IL-12)
dormancy: TNF-alpha, IFN-Gamma
dissemination: TH2 response (IL4, IL10)
