Immune Defence against Fungi

Question 1

What are fungi commonly like at mucosal sites?

Answer 1

Fungi are generally commensal at most mucosal sites (e.g. C. albicans in oral cavity and gastrointestinal tract)

Question 2

When does disease from previously commensal fungi occur?

Answer 2

• Immune status is compromised
• Barrier integrity is disrupted
• Microbiota balance is disrupted (e.g. by antibiotics)

Question 3

What are three common mucosal sites for fungal infections?

Answer 3

• Oral & GI in C. albicans
• Lung in A. fumigates & C. neoformans
• CNS in progressed C. neoformans

Question 4

What is the morphological plasticity of C. albicans?

Answer 4

Can switch between yeast (commensal) and hyphal (invasive) forms

Question 5

What is Dectin-1?

Answer 5

C-type lectin PRR that recognises B-glucans in fungal cell walls (e.g. in Candida & Aspergillus)

Question 6

What is Dectin-2?

Answer 6

Host C-type lectin PRR that recognises a-mannans (particularly in Candida)

Question 7

What are four innate immune cells important in protection against fungal pathogens?

Answer 7

• Epithelial cells
• Neutrophils
• Macrophages
• Dendritic cells

Question 8

What do epithelial cells use to detect fungal pathogens?

Answer 8

PPRs like Toll-like receptors and C-type lectin receptors that detect PAMPs from fungi (e.g. B-glucans, a-mannans, and other fungal carbohydrates)

Question 9

What do epithelial cells do once they detect a fungal pathogen?

Answer 9

Secrete proinflammatory cytokines
Produce antimicrobial peptides (like B-defensins)

Question 10

What is the role of neutrophils in anti-fungal immunity?

Answer 10

They are the essential first line of defense

Question 11

How do neutrophils kill fungal pathogens?

Answer 11

Via:
- Reactive oxygen species
- NETs
- Phagocytosis

Question 12

What do individuals with defective neutrophils have a susceptibility to?

Answer 12

Mucocutaneous candidiasis

Question 13

What is the role of macrophages against fungal infections?

Answer 13

• Proinflammatory cytokines
• Phagocytosis (particularly of yeast; less effective on hyphae)

Question 14

What is the importance of DCs?

Answer 14

Secrete specific cytokines that drive naive CD4+ T cells to become Th17

Question 15

What is the main transcription factor for Th17 cells?

Answer 15

RORyt- DC cytokines collectively push Th cells to express RORyt

Question 16

What is the importance of antibodies in clearing fungal infections?

Answer 16

Largely viewed to be of less importance compared to T cells.
However, emerging research has shown their increasing importance e.g. in opsonisation

Monoclonal antibodies are being explored as a possible treatment for Candida infections

Question 17

What are the main T cells involved in antifungal defence?

Answer 17

• Th17
• Th1

Question 18

What is the role of Th1 cells in antifungal defence?

Answer 18

Secretion of IFN-y that activates macrophages, enhancing their phagocytic ability

Question 19

What do Th17 cells do?

Answer 19

Produce IL-17A & F, and IL-22.
These:
- Recruit neutrophils
- Stimulate the release of antimicrobial peptides (particularly by epithelial cells)
- Maintain mucosal barrier integrity

Question 20

What would IL-17 pathway mutation result in?

Answer 20

A deficiency in crucial cytokines in controlling fungal infection- chronic candidiasis of mucocutaneous areas

Question 21

What are mucocutaneous areas?

Answer 21

Where a mucous membrane meets the skin

Question 22

What can C. albicans do to escape NETs?

Answer 22

Produce Nuc1 that can degrade NETs, allowing them to escape

Question 23

What are the different aspects of Aspergillus that need defending against?

Answer 23

• Inhaled spores (conidia)
• Hyphae

Question 24

How are conidia dealt with?

Answer 24

Alveolar macrophages can kill them via ROS and phagolysosomal enzymes

Question 25

How do macrophages deal with hyphal forms of Aspergillus?

Answer 25

It cannot handle hyphal forms well- needs help from neutrophils/activation by IFN-y

Question 26

How do neutrophils kill hyphae forms of Aspergillus?

Answer 26

- ROS burst - Degranulation - NETs

Question 27

What are some immune evasion techniques used by Aspergillus?

Answer 27

- Rodlet layer on conidia masks PAMPs (no recognition) - Gliotoxin inhibits macrophages and neutrophils

Question 28

What is the critical adaptive response, and primary immune effector for Aspergillus infections?

Answer 28

Adaptive = Th1 & Th17 Effector = Neutrophils

Question 29

What is the primary immune effector for Cryptococcus infections?

Answer 29

Adaptive = Th1 Effector = Activated (by IFN-y) macrophages

Question 30

Why do alveolar macrophages struggle to deal with Cryptococcus?

Answer 30

Their thick polysaccharide capsule largely inhibits phagocytosis. Cryptococcus can also live intracellularly.

Question 31

Why is Th1 important in fighting against Cryptococcus?

Answer 31

Secretes IFN-y which activates macrophages, enhancing their recognition, phagolysosome fusion, and production of ROS/RNS

Question 32

What is the trojan horse mechanism wrt Cryptococcus?

Answer 32

Cryptoccous can survive and replicate intracellularly within phagocytes like macrophages (through inhibition of phago-lysosome fusion). This can facilitate its dissemination, especially in crossing the blood-brain barrier (Cryptococcal meningitis)

Question 33

Other than Trojan Horse, what other immune evasion techniques does Cryptococcus have?

Answer 33

- Capsule masks PAMPs and prevents phagocytosis - Produces melanin which resists ROS