fungal infections

Question 1

Most ways fungal infections are spread

Answer 1

inhalation, from GI tract and microbiome, through skin

Question 2

Which four fungal species are the biggest systemic infections and killers?

Answer 2

pneumocystis spp.
Aspergillus spp.
candida spp. (part of the microflora)
Cryptococcus spp.

Question 3

What has/is driving systemic fungal infections?

Answer 3

HIV pandemic, medical immunosuppression and antimicrobial resistance.

Question 4

What are fungal associated drug targets?

Answer 4

fungal cell wall, DNA synthesis (pyrimidine analogs), and sterol synthesis at the ER.

Question 5

Which T cell immune responses are especially important for counteracting fungal infections?

Answer 5

Th1 (IFN-y) and Th17 responses are critical for fungal infections.

Question 6

What T cell responses may limit fungal response?

Answer 6

Tregs, and Th2 may be more pathogenic.

Question 7

Which innate cells especially important?

Answer 7

macrophages and neutrohphils (deficiecny causes susceptibility to aspergillus)

Question 8

Which TLRs are especially important for responding to fungal infections?

Answer 8

TLR2 and TLR4 which bind mannan on cell wall.

TLR7 and TLR9 sense fungal ssRNA and unmethylated CpG.

Question 9

What explains contradictory survival results for TLR2 KOs in fungal infections?

Answer 9

different strains have different cell wall compostions, which are recognised by different receptors.

Question 10

When/ who is TLR fungal reconition important for?

Answer 10

Not important in healthy individuals.

But if immunosuppressed play an important role.

Question 11

What other PRRs apart from TLRs are important recognisers of fungi?

Answer 11

C type lectin receptors (CLRs) which bind sugars (often found on fungi surfaces).

Question 12

What are the 4 soluble C type lectins that recognise mannan?

Answer 12

SP-A, SP-D
Galectin-3
MBL

Question 13

What do the three most important fungal CLRs, Dectin-1, MINCLE and Dectin-2 recognise?

Answer 13

Dectin-1 B-glucan
MINCLE- mannan
Dectin-2 hyphal mannan

Question 14

What does DC-SIGN and mannose receptor recognise?

Answer 14

DC_SIGN- mannan

mannose receptor- chitin.

Question 15

What molecule do Dectin-1/2 and MINCLE signal through?

Answer 15

Syk, which activates PKC and the CARD9-Bcl10-MALT1 complex.

Question 16

What variety of responses can Dectin-1 recognition of B-glucan trigger?

Answer 16

phagocytosis,
arachidonic acid metabolism (PGE and leukotrienes), respiratory burst and NET formation.
cytokine production and inflammasome activation
adaptive imunity Th17 and Th1 responses.

C

Question 17

What molecules downstream of Dectin-1 and Syk activate cytokines in response to B glucan?

Answer 17

PKC triggers CARD9-Bcl10-MALT1 then NF-KB (and capsase 8) actiaviton.

PLCy activation triggers calineurin and NFAT activation.

NLP3 inflammasome triggered (caspase 1).

Question 18

What Syk independent Dectin-1 pathway is there?

Answer 18

Raf- p65 and NF-kB activaiton.

Question 19

what two gene deficiencies sin humans caused susceptibility to fungal infections?

Answer 19

CARD9 ad Dectin-1 deficiencies.

Question 20

What is a non-carbohydrate fungal (CLR) receptor MelLec detect?

Answer 20

MelLec detects DHN-melanin

Question 21

What receptors can synergise with Dectin-1 to increase responses to fungi?
What pathogen and disease can this help resolve?

Answer 21

TLRs.

Synergistic signalling through TLR and Dectin-1 can help resolve chromoblastomycosis (caused by F. pedrosoi).

Question 22

What kind of pathology might fungal PRRs and TLR synergism be pathogenic?

Answer 22

In recognisiont of B-glucans and LPS in steroid resistant asthma.

Question 23

What fungal mechanism might accelearte pancreatic cancer?

Answer 23

Fungal dysbiosis can activate the MBL complement cascade which can accelerate cancer growth.

Question 24

How might alcohol damage and fungal dysbiosis be linked?

Answer 24

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.

Question 25

Apart from innate sensing mutations, PIDs that cause defects in what arms of immune response are assocaited with fungal infections?

Answer 25

Those affecting Th1 and Th17 response.
e.g. SCID and HIV cause loss of T cells.

STAT3 mutations that lead to Th17 deficiency in a hyper IgE syndrome.

mutations in IL12 receptor (TH1 response)

Question 26

What autoimmune condition associated with fugnal infection and why?

Answer 26

APECED, due to anti-IL17 antibodies.

And maybe because of exuberant IFN-y which disrupts epithelial barrier.

Question 27

What disease affecting respiratory burst is suceptible to which fungi?
A theory why?

Answer 27

CGD, suceptible to apergillus infection.

Maybe because ROS triggers a caspase and fungal programmed cell death- which would be defective in CGD patients.

Question 28

How can fungi evade immune responses?

Answer 28

changing morphology, with capsule (cryptococcus), shedding B glucan

Question 29

Which fungi can shed B glucan, and what does it use to help avoid dectin-1 detection?

Answer 29

Histoplasma produces Eng1 which can reduce surface B glucans.