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Rob's Microbiology MCD > Micro 1: Fungal Immunity > Flashcards

Micro 1: Fungal Immunity Flashcards

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Biology 101 flashcards
1
Q

Which fungi classes cause disease in humans

A

3 phyla causing disease in humans

Zygomycota
Basidiomycota
Ascomycota
bottom 2 more closely related

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2
Q

Give an example of ascomycota

A

Yeast
Candida
Aspergillus

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3
Q

Give examples of basidiomycota

A

Mushrooms

Cryptococcus

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4
Q

Fungi causing infections

A

Aspergillus (ascomycota)

Cryptococcus (basidiomycota)

Candida albicans (ascomcota)

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5
Q

How can aspergillus cause problems

A

Normally fine, most people inhale every day

Only a problem if you have no neutrophils

Can germinate (leading to fungal ball) 
and cause bleeding in LUNGS
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6
Q

How can Cryptococcus neoformans cause disease

A

Mushroom group (microscopic)

Fimbrae that allow it to adhere to surfaces

Commonest cause of death in HIV patients (subsaharan Africa)

Inhaled through lungs but can disseminate to brain if lack of CD4+ T cells

Leads to cryptococacal meningitis

Can then develop cryptococcomas (fungal ball) , and stroke like symptoms

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7
Q

What is cryptococcoma

A

Ball of fungus which has germinated.

CNS (cryptococcus neoformans)

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8
Q

How can candida albicans cause disease

A

Candida is commensal on skin and gut

But in immunocompromised/catheterised

Can get into the back of the eye creates mass

=candida endophthalmitis

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9
Q

Outline importance of innate immunity to fighting fungal infection

A

*Opsonization by pentraxin 3 and mannose-binding
lectin

  • Phagoctes first line of defence (so loss of neutrophils is a key risk factors)
  • NK cells provide early interferon-gamma

*A failure of innate immunity leads to adaptive
responses

  • Dendritic cells present antigen to T cells
  • Can lead to Th1, Th2 and Th17 responses
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10
Q

Why are NK cells important in cellular immunity to fungal infection

A

They produce IFN-g which primes macrophage to deal with fungus (i.e. TYPE II interferon)

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11
Q

Outlie the virulence of:

Candida, cryptococcus and aspergillus

A

Can start as unicellular organisms then become mutlicellular

▪Candidal dimorphism (yeast/hyphal forms) allows tissue invasion

▪Crytpococcus forms a capsule to evade phagocytosis

▪Aspergillus species inhaled as conidia, invade tissues as hyphae

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12
Q

How can fungi be sensed

A

Toll like receptors (innate receptor)

Losing the toll systems put you at high risk of fungal disease

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13
Q

What are c-type lectins

A

Part of immunoglobulin super family

Detect carbohydrate on fungal cell wall

Also important for phagocytosis of fungi (TLR cannot do it alone)

(inc. dectin 1 which sense 1,3 b glucans)

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14
Q

List the overall receptors important in fungal immunity

A

TLR, c-type lectins, DAMPs and scavenger receptors

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15
Q

T/F scavenger receptors normally phagocytose non-inflammatory materials

A

T

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16
Q

What receptor type is important for candida immunity. What happens without it

A

Dectin 1 (a c-type lectin). It binds candida.

Without dectin 1 cannot produce IL-6 or bind candida

Mutation results in chronic mucocutaenous canditis

Problem in stem cell transplants

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17
Q

What deficiencies could result in chronic mucocutaneous candidasis

A

Basically, it’s just telling you that c-type lectin is really importnat in fungal immunity.

Mutations and thus deficiency of Dectin 1, a c-type lectin, and CARD9, a protein in the downstream signalling pathays for many c-type lectins, can result in the chronic candida infection

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18
Q

What is worse, dectin 1 or CARD9 deficiency

A

CARD9, because this is the signalling molecule for the actiation of many receptors

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19
Q

Why is CARD9 required in fungal immuity

A

Functional Card9 is Required for TNFα Production in Response to βGlucan Stimulation

Required for T cell Th17 Differentiation in Humans (SHOWS THAT DEFECTIVE INNATE RECEPTORS MEANS THAT ADAPTIVE IMMUNE SYSTEM CAN THEN NOT BE TRAINED TO DEAL WITH THE FUNGAL IMMUNE SYSTEM)

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20
Q

Why is Th17 response importnat in fungal disease

What happens in response to CARD9 deficiency with Th17

A

Mucosal protection

But in CARD9 deficiency, Th17 does not differentiate properly (showing that innate immune reponse interacts with adaptive one)

And you don’t then get recruitment of neutrophls to the site of infection

and you get chornic mucocutaneous candidasis

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21
Q

What fungal infection is important in stem cell trnapsnatation

A

Apergillosis

(stem cell transplantation occurs in leukaemia. All your own bone marrow wiped out with txic drugs. Give someone else’s bone marrow. That bone marrow will act as your bone marrow, creating your red and white cells. But it will also attack your own immune system to destroy all of the bone marrow cancer)

But during that period of the transplanted bone marrow killing your bone marrow and then producing new cells, there are less neutrophils and less innate immunity, and these patents very susceptible to fungal infection including aspergillosus

TLR4 polymophoisms can alter risk of pulmonary aspergillosis in transpantation

22
Q

What is important in risk of invasive aspergillosis in stem cell transpantation

A

Dectin 1 and TLR4

23
Q

Mutations in which haemostasis related protein increases susceptibility to fungal disease

A

Plasminogen (as well as dectin1, TLR4)

24
Q

Why will fungal immunogenics be important

A

E.g in transplant patients you can look at their TLR4 phenotype and see if this is going to place them at a risk of a certain infection and then give prophylactic medication (ABs)

25
Q

What are important innate immunity cells in fungus infection

A

Both macrophages and neutrophils contribute to fungal immunity

However for Aspergillus neutrophils are of primary importance

26
Q

What happens if you took neutrophil away from lung and put aspergillus there

A

It would grow as it would in a test tube

Basically, without neutrophils aspergillus will grow so easily and body doesn’t really do anything with it

27
Q

Outline one way in which neutrophils deal with fungi

A

Neutrophl extracellular nets

DNA released by dead neutrophils and this binds the aspergillus (in this cause aspergillus fumigatus) and is very sticky

This is the reason for very sticky mucus in these sorts of infections

28
Q

Other function of DNA other than coding for proteins

A

Neutrophil extracellular trap

And, when released from cells, acts as a DAMP (along with histones, actin etc.)

29
Q

When do Th1 responses occur and when do Th2 responses occur generally

A

Th2 is development of allergic response i.e. eosinophil and mast cell degranulation

Th2 is promoted by worms and parisitic infections because they are too big to phagocytose, so Th1 response isn’t approrpiate

Th1 response occur against intracellular parasites such as bacteria and viruses which can be phagocytosed

30
Q

What determines whether the response to the fungus is Th1 or Th2

A

Dendritic cells cause either Th1 or Th2 response depending on whether it’s unicellular or multicellular

I.e
Candida yeasts= IL-12 (from Th1)
Candida hyphae=IL4/IL10 (from Th2)

Aspergillus conidia=IL-12 (from Th1)
Aspergillus hyphae=IL-4/IL-10 (from Th2)

More Th1 for unicellular more Th2 for multicellular

31
Q

Outline the T helper response to fungi

A

DEPENDS

on fungal morphogenesis.

At first, the fungi might be in the yeast form but then can take different forms (hyphae form/capsule)

Dendritic presentation determines T cell response

32
Q

What is the relevance of both Th1 and Th2 responses to fungal infection

A

They have both invasive infectious disease AND drive allergy including asthma

33
Q

Outline novel methods of treating fungal disease based on immunotherapy and gene editing

(not necessary just incase you stressed)

A

IMMUNOTHERAPY. T cell adoptive therapy.
In the stem cell transplant example, we said that patients were susceptible to aspergillus (and candida) after stem cell transplant. After taking stem cells from the donor, you can select for T cells with specific fungus binding receptors, and give these to the patient if they get fungal infection after the HSC transplant has occurred

Gene editing
There is mutation in NADPH oxidase which is present on plasma membrane of phagosome to generate reactive oxidants in the RESPIRATORY BURST to kill organisms phagocytosed by neutrophils for example. A boy who had mutation in this protein had chronic granulomatous disorder. They took out his bone marrow and gene edited all of the cells using a virus to correct the mutation. Then then killed all his other bone marrow cells that weren’t gene edited, re-infused the edited bone marrow cells which now contain functional NADH oxidase. There was restoration of neutrophil NET formation :)

34
Q

What is the importance of T cell interferon gamma

A

Adaptive T cell interferon-gamma responses augment host immunity to fungi

35
Q

For candida and aspergillus, neutrophls are importnat. What about for cryptococcus

A

Cryptococcus more in HIV patients.

CD4+ T cells more important

36
Q

Give examples of aspergillu environmental organisms

A

Aspergillus niger

Aspergillus fumigatus

Inhaled leading to fungal allergic airway disease. Spores get into lungs really easily

37
Q

T.f people with asthma due to fungi like aspergillus are getting it due to immunosupression

A

F they are getting it because of an exaggerated immune response

38
Q

Outline a type of fungal disease fo each category of hypersensitivity reacton

A

Type 1 (IgE/histamine mediated) –> allergic rhinitis, allergic asthma, ABPA

Type 2 –> unknown

Type III–> hypersensitivity pneumoniits/aspergilloma

Type IV –> hypersensitivity pneumonitis

39
Q

T/f there is just one allergen in fungi that causes hypersensitive response

A

F

40
Q

Outline why fungal allergens are confusing for immune system

A

Cross reactivtiy between candida allegens in the gut and breathed in allergens in the lung (immune system doesn’t know which it is responding to)

And

Because they are eukaryotic, some allergens from fngi have promoted autoimmue response against self antigens in the lung

41
Q

What leads to allergic and what leads to invasive fungal disease

A

Wheter host response is ineffective or exaggerated

42
Q

What type of hypersensitivity reactions are occurring in fungal infections

A

I, III and IV

43
Q

What is the primary driver of allergic fungal disease

A

Aspergillus

44
Q

What is ABPA

A

Allergic bronchopulmonary aspergillosus which causes IgE response and is a form of bronchiectasis

High eosinophil levels in peripheral blood

Loads of mucus

Overexagerated immune response

45
Q

Which conditions presispose to ABPA

A

Asthma or cystic fibrosis

46
Q

Radiological features of ABPA

A
  • Dilated bronchi with thick walls
  • Ring or linear opacities
  • Upper or central region predeliction
  • Proximal bronchiectasis
  • Lobar collapse due to mucous impaction (hyper dense mucus)
  • Fibrotic scarring
47
Q

What happens to size of airways with ABPA

A

DILATION (this is bronchiectasis)

Bronchiectasis is a long-term condition where the airways of the lungs become abnormally widened, leading to a build-up of excess mucus that can make the lungs more vulnerable to infection

Because of mucus plugging

48
Q

Management of ABPA

A

Corticosteroids

Itraconazole for steroid sparing effect (a triazole)

Recombinant IgE monoclonal antibodies

49
Q

What is an anti-IgE antibody

A

Omalizumab

50
Q

What is hypersensitivity pneumonitis

A

Fibrotic lung disease

Evidence for fungal sensitisation

51
Q

What is diagnosis of fungal hypersensitivity driven by

A

Diagnosis driven by skin test, IgE and IgM in clinical relevant populations

Rob's Microbiology MCD (6 decks)

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