Immunity to fungal infections

Question 1

What are the four main phyla of fungi and which most commonly causes human fungal infection?

Answer 1

Ascomycota – MAIN ONE
Basidiomycota
Zygomycota
Chytridiomycota (doesn’t really cause problems)

Question 2

Important types of fungi known to cause human infection include?

Answer 2

Candida, Aspergillus and Cryptococcus species

Question 3

Give examples of how the morphogesis of fungi contributes to its ability to cause disease in the host.

Answer 3

Candida albicans exist as single spores but they can become hyphae, which allows tissue invasion
Cryptococcus forms a capsule to evade phagocytosis
Aspergillus sp. are inhaled as conidia and invade tissues as hyphae

Question 4

What patients are at risk of fungal infection and why?

Answer 4

Fungal pathogens are largely opportunists, only causing infections and disease when host defences are breached.

Those at risk:

• Patients with cancer because often they are immunocompromised, either because of their underlying malignancy and/or the treatment for their disease.
• AIDS patients
• Transplant recipients

Those at highest risk:

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

Question 5

The immune response to fungi depends on what?

Answer 5

• species encountered
• anatomical site of infection
• fungal morphotype

Question 6

State the important antifungal effector cells which form the first-line of defence of phagocytosis.

Answer 6

Neutrophils, macrophages and monocytes

Question 7

As fungal cell walls are fundamentally different in their structure from human plasma membranes, what class of receptors are important in their detection?

Answer 7

Pattern recognition receptors of innate immunity

Question 8

What are the ligands present on nearly all fungi?

Answer 8

1,3 β-glucans
Mannans
Chitin

Question 9

List the PRRs for 1,3 β-glucans

Answer 9

Dectin-1
CR3 (CD11c/CD18)
CD5
CD36
SCARF1

Question 10

List the PRRs for Mannans

Answer 10

Mannose receptor (CD206)
DC-SIGN (CD209)
Langerin (CD207)
Dectin-2

Question 11

State the PRR for Chitin

Answer 11

Mannose receptor (CD206)

Question 12

Name another type of PRR involved in sensing other fungal components

Answer 12

Toll like receptors (TLRs)

Question 13

Name 2 deficiencies that are associated with an increased risk of mucocutaneous fungal infections (namely chronic mucocutaneous candidiasis)

Answer 13

Dectin 1 deficiency => e.g. vulvovaginitis & onychomycosis

CARD 9 deficiency (CARD9 is an adaptor protein in the downstream pathway of Dectin 1)

Question 14

Dectin 1 deficiency causes…

Answer 14

• impaired macrophage IL-6 production and binding in response to fungal infections.
• increased susceptibility to invasive aspergillosis in stem cell transplants.

Question 15

CARD-9 is required for…

Answer 15

• TNFa production in response to b-glucan stimulation.

- T-cell Th17 differentiation

Question 16

Mutations in what three things confer increased susceptibility to fungal disease?

Answer 16

TLR4
Dectin 1
Plasminogen

Question 17

Which PRR is actively recruited to Aspergillus fumigatus phagolysosomes?

Answer 17

TLR9

Question 18

What can plasminogen directly bind to?

Answer 18

Aspergillus fumigatus conidia

Question 19

What do neutrophils release that enable them to trap Aspergillus?

Answer 19

NETs - chromatin “nets”.

These also act as “danger signals” and recruit’s effector cells to the area as well.

Question 20

Describe how fungal morphogenesis governs the dendritic cell modulation of adaptive immunity.

Answer 20

Hyphal forms = Th2 response

Conidium = Th1 response

Question 21

What cytokine therapy has been shown to enhance clearance of invasive fungal infection?

Answer 21

IFN-gamma

Question 22

Describe the principles of adoptive immunotherapy for fungal infection.

Answer 22

If a patient is receiving a stem cell transplant, you can generate anti-fungal T cells, which can be cultured in large numbers and administered to the patient

Question 23

Give an example of gene therapy for chronic granulomatous disorder.

Answer 23

Restoration of gp91 function
This is involved in the generation of NADPH oxidase – this generates reactive oxygen species, which is required to kill microbes
NOTE: another type of gene therapy = restoration of neutrophil NET formation

Question 24

What types of hypersensitivity reaction are associated with fungal allergies?

Answer 24

Type 1, 3 and 4

Question 25

What are two predisposing conditions for allergic bronchopulmonary aspergillosis (ABPA)?

Answer 25

Asthma

Cystic fibrosis

Question 26

What is the obligatory criteria for ABPA?

Answer 26

Total baseline serum IgE > 1000 IU/ml

Positive immediate hypersensitivity skin test or Aspergillus-specific IgE

Question 27

List some supportive criteria for ABPA.

Answer 27

Eosinophilia > 500 cells/ul
Serum precipitating or IgG antibodies to Aspergillus fumigatus
Consistent radiographic abnormalities

Question 28

List some radiological features of ABPA.

Answer 28

• Dilated bronchi with thick walls
• Proximal bronchiectasis
• Ring or linear opacities
• Upper or central region predilection
• Lobar collapse due to mucous impaction
• Fibrotic scarring

Question 29

What might be seen in a CT scan of a patient with ABPA?

Answer 29

Hyper dense mucous sign

Question 30

Describe the main treatment options for ABPA.

Answer 30

Corticosteroids
Itraconazole may be used as a steroid-sparing agent
Recombinant anti-IgE antibodies (omalizumab) may be useful

Question 31

List three other examples of fungal allergies, including associated features of each.

Answer 31

Aspergillus rhinosinusitis:

• May be allergic or invasive
• Obliterated sinuses
• Treated with oral corticosteroids

Severe asthma with fungal sensitisation

• Fungal sensitisation as a potential cause of severe asthma
• Requires exclusion of ABPA
• Treatment with anti-fungal unclear

Hypersensitivity pneumonitis (extrinsic allergic alveolitis) 
- Allergy requires long-term exposure to allergen (often occupational)

Question 32

What test is used to diagnose fungal allergies?

Answer 32

Skin prick testing

Question 33

Which type of hypersensitivity is each of the previously mentioned fungal allergies?

Answer 33

ABPA – type 1 or 4
Asthma – type 1
Rhinitis – type 1
Hypersensitivity pneumonitis – type 4