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Microbiota On Mucosal > C5- Virulence Determinants In Candida > Flashcards

C5- Virulence Determinants In Candida Flashcards

1
Q

Give some examples where candida can outgrow

A

Antibiotics, pid/genetic defect, oestrogen/glycogen increase during pregnancy

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2
Q

What are the 4 stages of infection

A

Stage 1- colonisation through adhesion
Stage 2 - superficial infection: epithelial penetration and nutrient acquisition through host protein degradation

Stage3 - deep infection : penetrate tissues and vascular system and immune
evasion in blood

4- disseminated disease eg in organs like kidney via endothelial adhesion

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3
Q
  1. Adhesins

What are the main components of adhesins on outer cell wall

A

ligand binding domain (effector domain)

Then low complexity domain with ser/thr tandem repeats (often)

Can be anchored by gpi anchor to cell wall

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4
Q

What are the 3 families of adhesins in Candida albicans and what they bind (not in benign yeast)

A

Als family (9 genes) - epi and endothelium
Hwp1 family (5members) - saliva coated oral cavity and normal epi cells
Iff family (12 members)- epithelium

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5
Q

Looking at genome sequences (from previous lecture). What is evident about these family of genes

A

There is gene expansion/ duplication events - potentially with different affinity capacities like bspA in trichomonas

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6
Q

What agglutinin like gp are there in als family

A

Als 1 and 5

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7
Q

Explain their c terminus and the role it plays

A

C terminus is the low complexity ser/thr glycosylations allowing extension into environment

Threonine rich tandem repeat region forms amyloid like structure which has aggregation capacity (will aggregate with other fungi or bacteria esp in biofilms)

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8
Q

What is their n terminus/ effector domains like

A

Ig-like domains which swivel and act as a cavity for host peptides/ligands

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9
Q

Are they specific or broad binding

A

B-road s

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10
Q

Is it held by gpi anchor

A

Yes

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11
Q

Which adhesins important for biofilm formation on biotic / mucosal surfaces or abiotic like catheters

A

Als3 and hwp1

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12
Q

What are biofilms for

A

Evade immune system and increased resistance

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13
Q

Can they interact with other microbes

A

Yes bacterial-fungi interactions

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14
Q

What protein for drug resistance is upregulated in biofilms

A

Drug efflux pumps

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15
Q

Give a biofilm example in other candida species suggested important in Ibd (hoarau 2016)

A

C tropicalis with s marcescens and E. coli

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16
Q

What are invasins

A

Adhesins als3 and ssa1 which are specifically important for mediating fungal endocytosis for invasion eg for nutrient acquisition

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17
Q

What do they bind

A

E cadherin on epi or n cadherin on endothelial

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18
Q

What other way to invade is there

A

Penetration through hyphae

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19
Q

2 - morphogenesis

A
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20
Q

What sorts of things does morphogenesis occur to (pseudo with septation division or hyphae )

A

Ph (7 in blood = hyphae) and dfg16 alkaline example thewes 2007

, nutrients, co2 in blood, temperature (37c) , serum in blood

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21
Q

What is the diff between pseudo and hyphae

A

Pseudo have a construction at site of septation(between mother and daughter)

Cannot see distinct cells in hyphae and they are much thinner

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22
Q

What is filamentation crucial for

A

Access to blood for systemic
Escape from phagocytosis
Infection of internal organs - thewes found dfg16 for kidneys of mouse and pig

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23
Q

What happens when engulfed in phagosome

A

Hyphae switch occurs to kill them and escape

24
Q

What is the ras positive pathway of filamentation

A

Ras gtp active

Will activate adenylyl cyclase cdc35 to produce camp from atp

Camp activated pka will then phos tf efg1 which induces expression of ume6 hyphae specific gene

25
Q

What is the mapk pathway/cph1 activation instead for ume6 expression

A

Mapk pathway activation by ras-gtp
Ste11 mapkkk
Hst7 mapkk
Cek1 mapk

will phosphorylate tf cph1 which also induced ume6 gene

26
Q

What happens to double mutants of efg1 or cph1 (c4 suggests both mouse and zebra fish survival studies)

A

Form Budding avirulent forms

27
Q

Which 2 proteins recruit tup1 txn repressor to block hyphae genes like ume6

A

Rfg1 and nrg1

28
Q

What is the evidence dimorphism is required not just hyphae

A

Mutant tup1, rfg1 or nrg1 also reduces virulence of the fungi

29
Q

Ume6 and virulence evidence study

Using ume6 regulated under doxycycline (if dox present represses ume6) in mouse models injected with candida strains (engineered)
What we’re the histologixal and survival results

A

After 30 days - 70% survival in dox+ / 0 Survivial when ume6 wasn’t repressed and was expressed highly in lack of dox presence

Kidney histology showed lack of dox meaning ume6 exp allowed filamentation - showing it promotes virulence

30
Q

What sorts of genes are hyphae specific/ upreg in hyphae form

A

Als3 (invasins and biofilms)
saps and hwp1 (biofilm)

31
Q

So how do we know it isn’t because of these genes not the actual shape causing virulence

A

Hgc1 (cell cycle protein) protein mutant which is involved in hyphae formation prevents shape change but had no effect on these genes eg hwp1 still high

Still show reduced ability to colonise kidneys of mice / invasiveness and
Reduced ability to kill the mice too (consistent with ume6 study)

32
Q

How does quorum sensing (of both bacterial and fungal origin) affect hyphae growth aswell

A

Dense populations will release farnesol quorum molecule which will prevent hyphae formation for better colonisation of mucosal surfaces

33
Q

How does farnesol block hyphae growth (showing potential importance of dense bacterial populations on inhibiting hyphal formation)

A

It acts to block adenyl cyclase cdc35 stopping camp activation of pka and efg1 tf

34
Q

What 3 types of secreted enzymes do they have for nutrient acquisition, and tissue invasions - in candida are expressed on hyphal tip

A

Phospholipase (a,b,c,d classes) -only B are extracellular

Secreted aspartyl proteinase (saps)

Candidalysins

35
Q

What 2 Phospholipase B class are shown as virulence factors on the tip of hyphae cells to breakdown cell membranes

A

Plb1 and 5

36
Q

How many genes are there for saps (gene duplication example again) and the main differences

A

10

9+10 are cell surface gpi anchored

Some are expressed in yeast to hyphae growth eg sap6

Some in yeast cells eg sap2 I.e more acidic ph than sap6

Can work at different ph
Different substrates of proteins

37
Q

How does internalisation of saps 2 and 6 cause apoptosis and inflam response characteristic of vaginal candidiasis

A

Activation of the nlrp3 inflammasome
Caspases = apoptosis

38
Q

Which highly expressed hyphae protein is processed into 8 peptides including candidalysin

A

Ece1

39
Q

What does candidalysin toxin do

A

Forms pore within membrane causing permeability
Also induced ap-1 tf c-Fos causing cytokines and chemokine exp for inflammation

40
Q

Give an example of when this would happen

A

Inadequate NETs or phagocytosis

41
Q

4- fitness traits

A
42
Q

Give some fitness trait examples needed to survive a lot of environments

A

Evade host mechanisms eg ros/stress response
Adequate nutrient acquisition/metabolic change
Ph adaptation
Metal acquisition

43
Q

How is h202 formed at macrophage and neutrophils

A

NADPH oxidase complex forms and produces superoxide which is converted to h202

44
Q

What does stress activated c.albicans hog1 kinase do in response to h202 (aswell as cap1 tf)

A

Upon stress (ox or osmotic) becomes phos and activated by h202
Translocation into nucleus

Induces cell responses downstream crucial for survival (mutants are not able to survive under conditions of ox stress)

45
Q

What other enzymes to detoxify ros do they have

A

Sod , tsa (thiol specific antioxidant) and sod5, catalase

46
Q

Which tf is important for exp of all of these under ox stress and how

A

Cap1

When it becomes oxidised, the cys rich domains change conformation which mask it’s nuclear export sequence

Starts to accumulate in the nucleus

47
Q

Similar to hog1 mutants, what happens to cap1 mutants exposed to h202

A

Reduced survival / killer

48
Q

What happens in wt hog1 vs mutant systemic mice modes

Also what happens in macrophage modelling when both are knocked out

A

Hog1 Wt causes reduced survival in mice
Compared to 100% survival in hog1 mutants = avirulent

In macrophages with candida ko for both hog1 and cap1 there is a lack of filamentation and also reduced macrophage killing

49
Q

Which human kinase similar to hog1 kinase suggests we could potentially use the inhibitors we have for cancer treatment for hog1 inhibition too - currently testing if it works

A

P38 kinase (inhibitors admin bc involved in tumour progression)

50
Q

Which adhesin/invasin can steal fe from ferritin from host

A

Als3

51
Q

What do they have to acquire zinc

A

Sincophore pra1

52
Q

How is it suggested under starvation, cells can induce hyphae growth (for cell invasion/nutrient acquisition) through alkalinisation (dfg16 can induce this)

A

Production of ammonia from aa uptake by deamination = released and causes alkalinisation
(Dfg16 mediated filamentation thewes 2007)

53
Q

Although superficial infections like thrush and oral candidiasis are very common; what happens in systemic disease in Immunocompromised

A

Can overgrow/ colonise different organs like eye, brain, kidney and cause organ failure and death

54
Q

How was pepstatin used to confirm that saps are virulence factors needed for tissue invasion

A

Injected candida with pepstatin sap inhibitor into mice

Found reduced tissue invasion and reduced systemic candidiasis

55
Q

Which protein present in the ecm of fungal biofilms which block neutrophil ros mediated killing

A

B glucans

Microbiota On Mucosal (22 decks)

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