fungal infections Flashcards
(29 cards)
Most ways fungal infections are spread
inhalation, from GI tract and microbiome, through skin
Which four fungal species are the biggest systemic infections and killers?
pneumocystis spp.
Aspergillus spp.
candida spp. (part of the microflora)
Cryptococcus spp.
What has/is driving systemic fungal infections?
HIV pandemic, medical immunosuppression and antimicrobial resistance.
What are fungal associated drug targets?
fungal cell wall, DNA synthesis (pyrimidine analogs), and sterol synthesis at the ER.
Which T cell immune responses are especially important for counteracting fungal infections?
Th1 (IFN-y) and Th17 responses are critical for fungal infections.
What T cell responses may limit fungal response?
Tregs, and Th2 may be more pathogenic.
Which innate cells especially important?
macrophages and neutrohphils (deficiecny causes susceptibility to aspergillus)
Which TLRs are especially important for responding to fungal infections?
TLR2 and TLR4 which bind mannan on cell wall.
TLR7 and TLR9 sense fungal ssRNA and unmethylated CpG.
What explains contradictory survival results for TLR2 KOs in fungal infections?
different strains have different cell wall compostions, which are recognised by different receptors.
When/ who is TLR fungal reconition important for?
Not important in healthy individuals.
But if immunosuppressed play an important role.
What other PRRs apart from TLRs are important recognisers of fungi?
C type lectin receptors (CLRs) which bind sugars (often found on fungi surfaces).
What are the 4 soluble C type lectins that recognise mannan?
SP-A, SP-D
Galectin-3
MBL
What do the three most important fungal CLRs, Dectin-1, MINCLE and Dectin-2 recognise?
Dectin-1 B-glucan
MINCLE- mannan
Dectin-2 hyphal mannan
What does DC-SIGN and mannose receptor recognise?
DC_SIGN- mannan
mannose receptor- chitin.
What molecule do Dectin-1/2 and MINCLE signal through?
Syk, which activates PKC and the CARD9-Bcl10-MALT1 complex.
What variety of responses can Dectin-1 recognition of B-glucan trigger?
phagocytosis,
arachidonic acid metabolism (PGE and leukotrienes), respiratory burst and NET formation.
cytokine production and inflammasome activation
adaptive imunity Th17 and Th1 responses.
C
What molecules downstream of Dectin-1 and Syk activate cytokines in response to B glucan?
PKC triggers CARD9-Bcl10-MALT1 then NF-KB (and capsase 8) actiaviton.
PLCy activation triggers calineurin and NFAT activation.
NLP3 inflammasome triggered (caspase 1).
What Syk independent Dectin-1 pathway is there?
Raf- p65 and NF-kB activaiton.
what two gene deficiencies sin humans caused susceptibility to fungal infections?
CARD9 ad Dectin-1 deficiencies.
What is a non-carbohydrate fungal (CLR) receptor MelLec detect?
MelLec detects DHN-melanin
What receptors can synergise with Dectin-1 to increase responses to fungi?
What pathogen and disease can this help resolve?
TLRs.
Synergistic signalling through TLR and Dectin-1 can help resolve chromoblastomycosis (caused by F. pedrosoi).
What kind of pathology might fungal PRRs and TLR synergism be pathogenic?
In recognisiont of B-glucans and LPS in steroid resistant asthma.
What fungal mechanism might accelearte pancreatic cancer?
Fungal dysbiosis can activate the MBL complement cascade which can accelerate cancer growth.
How might alcohol damage and fungal dysbiosis be linked?
Alcohol weakens epithelial tight junctions, fungi B glucans can leak through portal vein and bind CLEC7A receptors on kupffer cell to activate IL-1B.
Promotes liver damage.
