1. Immunity to fungal infections Flashcards

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1
Q

What causes pneumocystis pneumonia (PCP) and what is it associated with?

A
  • Pneumocystis jirovecii

* Associated with AIDS

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2
Q

What patients are at particular high risk of fungal infections?

A
  • Patients with prolonged and profound neutropenia after treatment with highly cytotoxic chemotherapy for haematological malignancies
  • Recipients of haematopoietic stem cell transplantation
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3
Q

How can fungal morphology affect the host response?

A

Larger sized (e.g. hyphae) preclude effective ingestion compared to yeasts and spores

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4
Q

Which cells have a role in linking innate and adaptive response to a range of pathogenic fungi?

A

Dendritic cells

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5
Q

Which cell type predominates in protective responses to various fungal infections, and which cytokine is important in this response?

A
  • Th1 type CD4+ T cell

* interferon-γ

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6
Q

Is innate or adaptive immunity more important in fungal infection?

A

Innate

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7
Q

Outline the cellular immune response to fungal infection

A
  • Opsonisation by pentraxin 3 and mannose-binding lectin
  • Phagocytes - first line of defence
  • NK cells - provide interferon-γ

• Failure of innate immunity leads to adaptive responses:

  • dendritic cells influence T cell differentiation
  • Th1 and Th17 play a role
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8
Q

What is Candidal dimorphism?

A

Grows in yeast and hyphal forms - allows tissue invasion

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9
Q

In what form does Aspergillus invade tissues?

A

Hyphae

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10
Q

How are fungal cells detected?

A
  • Cell walls sensed by pattern recognition receptors

* Toll like receptors

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11
Q

How are Toll like receptors (TLR) important in fungal immunity and complement?

A
  • Sense fungal components
  • Expressed on sentinel cells (macrophages and dendritic cells)
  • Activate immune cell responses - recruiting neutrophils and monocytes using cytokines, chemokines etc.
  • Complement activated - opsonisation due to deposition of C3b on fungal surface
  • Recruitment of inflammatory cells due to C3a and C5a generation
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12
Q

Which complement pathways can fungi activate?

A

Classical, alternative and lectin

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13
Q

What complement activity are fungi resistant to?

A

Complement-mediated lysis (due to thick cell wall)

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14
Q

Which antibodies in normal human serum are involved in a fungal cell response and how?

A
  • Antibodies to fungal cell wall components
  • Particularly mannans - can initiate classical pathway activation upon binding
  • May directly opsonise fungi for recognition by phagocytic Fc receptors (FcRs)
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15
Q

When does activation of the lectin pathway occur (with reference to mannans)?

A

When recognition of exposed mannans by mannose-binding lectin (MBL) triggers MBL-associated serine proteases

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16
Q

Summarise Human Dectin 1 Deficiency

A
  • HD1 is normally important in the phagocytosis of Candida and the immunity to chronic mucocutaneous candidiasis
  • Loss of function mutation - mendelian susceptibility to chronic mucocutaneous cadidiasis
  • Homozygous mutation - reduced inflammatory response via IL-6
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17
Q

Summarise Human CARD9 deficiency

A
  • CARD9 is an adaptor molecule downstream of C-type lectins
  • Required for TNF-alpha production in response to beta-glucan stimulation
  • Required for T cell Th17 differentiation
  • CARD9 deficiency patients are susceptible to mucosal and invasive infection
  • Chronic mucocutaneous cadidiasis
18
Q

What can the TLR4 loss of function mutation cause?

A

Increased risk of aspergillosis

19
Q

How can we predict which fungi someone will be most susceptible to?

A

Finding a patient’s immunogenomics

20
Q

Which immune cells are of primary importance for aspergillus?

A

Neutrophils

21
Q

Are macrophage-depleted mice susceptible to aspergillus fumigatus infection?

A

No, neutrophils are important

22
Q

What different responses are generated if you feed dendritic cells with unicellular fungal forms (e.g. yeast) or multicellular (hyphal) forms?

A
  • Unicellular - Th1 adaptive response, typified by IFN-γ

* Multicellular - Th2 adaptive response, typified by IL-4 and IL-10

23
Q

What pathogens is Th2 normally associated with?

A

Worms, but also deals with hyphae as they are too large to be phagocytosed

24
Q

What is Th1 normally mediated by?

A

Neutrophils and macrophages - resulting in phagocytosis

25
Q

Can fungi lead to a hypersensitivity?

A

Can cause allergies
• 5-10% of asthmatics have fungal driven asthma
• Severe dermatitis can be due to fungus on the skin

26
Q

Why is sputum sticky during a chest infection?

A

Neutrophil nets
• Extracellular fibres mainly comprised of neutrophil DNA
• Bind to extracellular pathogens and prevent them from replicating
• Net is sticky - reason for sticky sputum during chest infection
• Deficiency of these increases infection risk

27
Q

What is chronic granulomatous disease, its cause and effect?

A
  • Loss of gp91 function
  • Defects in NADPH oxidase enzyme
  • This is important for the generation of reactive oxidative species
  • Neutrophils can’t kill ingested pathogens

• Susceptibility to invasive fungal infections - particularly Aspergillus

28
Q

How can we restore the function of gp91 in CGD?

A

Gene therapy

29
Q

What is ABPA?

A
  • Allergic bronchopulmonary aspergillosis
  • Associated with asthma
  • Brochiectasis - airway gets wider and more prone to infections
  • Normally type I hypersensitivity (but can by type IV)
30
Q

How often are fungal spores inhaled?

A

Daily - response depends on person (ineffective, normal or exaggerated)

31
Q

What are predisposing conditions to ABPA?

A

Asthma or CF

32
Q

What is the obligatory criteria for ABPA?

A
  • Total baseline serum IgE > 1000 IU/ml

* Positive immediate hypersensitivity skin test or Aspergillus-specific IgE

33
Q

What is supportive criteria for ABPA (more than 2 present)?

A
  • Eosinophilia
  • Serum precipitating or IgG to aspergillus fumigatus
  • Consistent radiographic abnormalities (dilated bronchi with thick walls, fibrotic scarring etc.)
34
Q

How is ABPA managed?

A
  • Corticosteroids
  • Itraconazole (steroid sparing)
  • Reduction in circulating IgE
  • Recombinant IgE monoclonalantibodies (omalizumab)
35
Q

What is hypersensitivity pneumonitis (aka. extrinsic allergic alveolitis)?

A
  • Allergic response requiring long-term allergen exposure (often occupational)
  • Cell-mediated delayed sensitivity reaction
  • Allergen-specific precipitins usually present
36
Q

Which fungus is the most common cause of death in HIV patients?

A
  • Cryptococcus

* Inhaled through lungs but can disseminate to the brain if there is a lack of CD4+ => fungal meningitis

37
Q

What does candida albicans effect?

A
  • Found on skin, behaves like staphylococcus
  • Also found in GIT (low pH of stomach)
  • Commensal, but catheter/immuno-compromisation can lead to systemic infection
38
Q

Describe the morphogenesis of candida

A
  • Originates from parent yeast cell
  • Forms multicellular hyphae to allow tissue invasion
  • Usually in lungs
39
Q

Describe the morphogenesis of cryptococcus

A
  • Tends to stay unicellular in host

* Forms a protective capsule to evade phagocytosis - full of complex carbohydrates

40
Q

Describe the morphogenesis of aspergillus

A
  • Similar to candida
  • Spores germinate once in lungs, into hyphae
  • Difficult to destroy
41
Q

What do C-type lectins sense in fungi?

A

Carbohydrates in fungal cell wall