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Microbiota On Mucosal > C4- Fungi-immunity And Genetics > Flashcards

C4- Fungi-immunity And Genetics Flashcards

1
Q

What do most prr use as adaptors for nfkb txn

A

Myd88

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2
Q

What is the importance of prr in fungi (opportunists depend on defects in these responses)

A

Th1 diff, th17, treg(if tlr2)

Also induce respiratory burst

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3
Q

What does tlr4 recognise and in heterodimer with what

A

Glucoronoxylomannan gxm
particularly hyphae responsive
Also outer cell mannans from cell wall (o linked vs MR n linked)

In the tlr4-md2 complex

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4
Q

What does this signalling help differentiate important to stop cryptococcal meningitis

A

Th1 through ifny and il12 (via nfkb)

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5
Q

What recognises n linked mannans

A

MR

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6
Q

What are the 2 major co receptors of tlr which work together

A

Decrin 1 ctl for b1,3 glucan and mr

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7
Q

What’s the diff between tlr ,7 and 9

A

Tlr7 recognises ssrna of candida

Tlr9 recognises all dna e

Eg during phagocytosis

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8
Q

Phagosome maturation and acidification stopped by ca and cf means what

A

Immune evasion through tlr7 and 9

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9
Q

Why is tlr2 useful

A

Recognition of phosholipomannans

It helps to dampen responses through treg differentiation

Does this through mapk signalling (rather than nkfb) tgfb / il10 induction

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10
Q

Which th is required for fungal clearance eg during allergic aspergillosis

A

Th17 through il23 induction by prr

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11
Q

Which damps proteins released during inflammation or tissue damage and what sensed by to promote clearance

A

S100b protein

Tlr2

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12
Q

What is the evidence that over stimulation of tlr9 or any is bad

A

Snp in tlr9 sensing dna can increase nfkb binding affinity and is linked to ABPA

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13
Q

Snp in what inflammasome associated with recurrent vaginal candidiasis

A

Nlrp3

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14
Q

What changes happen during Ibd

A

Increased candida and sach in gut

colonisation in gut and asca antifungal ab

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15
Q

What sort of diet alterations have impact

A

and plant based increase candida vs penecilum in meat diet

High carb diets cause overgrowth

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16
Q

What complex is recruited by syk downstream of decrin 1 through signalling

A

Card9 adaptor protein, bcl10, malt1

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17
Q

What tf is induced by this and what differentiation primarily does this cause

A

Nfkb

Il23/6 for th17 differentiation
For NETs, phagocytosis and b defensin via il22

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18
Q

What does syk induce directly for clearance

A

Respiratory burst and phagocystosis

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19
Q

What does resp burst link to

A

Inflammasome nlrp3 activation and binding to Asc and caspases 1 for Il1b

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20
Q

Dysbiosis linked to antibiotics causes what which can trigger Ibd aswell as genetics

A

Candida outgrowth due to loss of commensal control

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21
Q

Give 2 genetic Ibd examples of poor fungal control

A

Decrin 1 snp linked to severe form of UC
Card9 linked to uc and crohns

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22
Q

Which immune response impaired by the card9 response

A

Th17 also phagocytosis in decrin snp

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23
Q

Fungal virulence determinants

A
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24
Q

How can comparative genomics be used to determine virulence traits

A

Identify species specific genes in the genomes of the 3 fungal opportunists

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25
Q

How many genes with no known function or orthologue in sacharomyces found in c albicans which could be for virulence

A

1000

26
Q

How many af specific genes with pathogenic function are there not in benign yeast like neosartorya fischeri

A

Around 700

27
Q

Do they have shared genes for virulence like the spi in diff bacteria

A

Non are identified yet

28
Q

What is it suggested they do instead to cause virulence

A

Adapt conserved parhways eg carbohydrate metabolism pathways

29
Q

What 2 other approaches can be done to find virulence traits

A

In vivo indetificatikn of genes

Or study of mutant libraries from insertational mutagenesis

30
Q

How did thewes 2007 examine transcriptomic profiles of a highly invasive candida strain vs less invasive

A

Inject mice models and study liver invasion ana take rna samples at diff time points

Because quite small tissue you can’t get replication in tranxriptomic data so also used ex vivo pig liver

Or remove liver from pig and topically add both candida
Also looked at transcriptimic profiles at diff time points

31
Q

What did they find comparing virulent strain with non virulent

A
32
Q

How could you identify genes expressed at diff time points of the sc5314 strain

A

Take rna samples at diff time points and sequence them

33
Q

How many genes found expressed during time points of infection in ex and in vivo both models and how many were sc5314 specific

A

63

5 specific

34
Q

Give example of one gene and how they tested this further. Also give example of a protein downregulated in these mutant types

A

Dfg16 plasma membrane protein required for filamentation in response to change in ph alkaline

First confirmed it’s expression on the plasma membrane

To analyse the function deleted Dfg16 and found mutants were not able to form hyphae in alkaline conditions anymore

Looked at effect of Dfg16 deletion and found that iron permease ftr1 was downregulated. This would usually be important in alkaline conditions as these conditions cause iron starvation

Suggests as well as filamentation process, Dfg16 induced exp of these survivial proteins

35
Q

Does transcriptional profiling prove it is involved in virulence

A

No only looks at expression

36
Q

Why is insertational mutagenesis easier with glabrata than albicans

A

Haploid so only one copy of interest gene vs diploid need to ko 2

37
Q

What sort of marker gene from yeast doen for IM

A

Ura3

38
Q

A library of how many homozygous mutants of c albicans used for key study in 2010

A

674

39
Q

What 3 things can they be screened for

A

Morphogenesis , infectivty/growth defects eg iv in mouse kidney, proliferation screening (growth defects)

40
Q

How did they measure infectivity in kidney of mice

A

Inoculated mice with 48 mutants at a time

Then removed kidneys later and extracted dna for qpc

Determine mutant relative abundance using qpcr after dna extraction from mouse kidney

If lower abundance than wt = defective durinf infection and gene would be important

41
Q

How many genes found for impaired infectivity vs morphogenesis vs proliferation and what were the conclusions from this

A

115 impaired infectivity
vs 133 for morphogenesis
68 for proliferation

Many of the genes were non overlapping

First study which concluded that impaired growth or morphogenesis does not always impair infectivity

42
Q

Give example of the imapired infectivity- specific genes (not overlapping with morphogenesis or prolifedation6

A

Sphingolipid biosynthesis impairement

43
Q

How was the identification of the sphingolipid parhway mutant important for infectivity been proven relevant for new antimycotics (like hsp90, and gpi deletions/defects in drug lecture)

A

Screened through HtS many molecules to find 2 potent inhibitors which work in animal models against Cn and ca = new Antimycotics currently in clinical trials

44
Q

Experimental models to study virulence

A
45
Q

How are cn and af administered to disseminated mice models vs ca

A

Inteanasally imahlation

Vs iv injection into tail vein

46
Q

How can you study virulence form the mouse

A

Study survival rates mutant vs wt eg dox ume6 and

tissue burden (cfu/g) eg kidney effects eg Hgc1 analysis

47
Q

What is galleria mellonella (a mini host alternative to mouse)

A

Wax moth larvae

48
Q

How can you inject and study survival

A

Larva taken from galleria and injected through a proleg to monitor survival

49
Q

How can c elegans be given fungi to monitor survival

A

Can be gfp-linked fungi and fed to nematodes

50
Q

Which 2 genes using celegans found important for killing of c elegans (mutant screening)

A

Ada2 and cas5 for hyphae formation

51
Q

Which other model can be used which is first vertebrate with both innate and adaptive unlike the other minibost

A

Zebra fish

52
Q

How are they infected

A

Injected into larval hindbrain ventricle

53
Q

Which tf for filamentation found important in mice was replicated in zebra fish

A

Cph1 and efg1

54
Q

What is the best incvitro model to study mucosal surface interactions

A

Reconstituted human epithelium

Cell lines cultured on polycarbonate filters

55
Q

How can you quantify adhesion through RHE

A

Count cfu when cultured to see how much fungi adhesion

56
Q

How can you quantify invasive ness/ penetrance using rhe

A

Can assay number of fungi cells that penetrate the rhe matrix (filamentation process)

57
Q

Can you test mutant libraries using rhe for adhesion/penetration

A

Yes

58
Q

Which pm protein found in the 5 unique genes for sc5314 strain was found to be important (thewes 2007) also in the study for penetration

A

Dfg16

59
Q

How else was Dfg16 studied for virulence after RHE studies for more evidence of virulence

A

Disseminated mouse model where mutant showed increased survival time of mouse

60
Q

Through study into ca genetic mutants of mannans (no O linked or n lined) and also prr ko mice what was found

A

Found tlr4 for o linked, MR for n linked and then decrin 1 are major for CA response

61
Q

What alteration causes overgrowth of candida in ugt

A

Oestrogen production during pregnancy

Hiv immunodeficiency

Lactobacillus loss

62
Q

What was the first model which you could study candida/macrophage interactions because they were transparent so could use tags

A

Zebra fish

Microbiota On Mucosal (22 decks)

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