Immunity to fungal infections

Question 1

how do cells develop immunity to fungal infection?

Answer 1

• Fungi are made more susceptible to phagocytosis by pentraxin-3 and mannose-binding lectin (MBL)
• the cells involved in providing immunity to fungal infections are the following:
• Phagocytes – are the first line of defense
• NK cells – provide early INF-gamma
• Dendritic cells – influence T-cell differentiation. Th1 and Th17 cells.

Question 2

how do specific fungal spores become more infectious? x3

(virulence)

Answer 2

Candida – dimorphism allows tissue invasion

Cryptococcus – capsule evades phagocytosis

Aspergillus – inhaled as conidia, invade as hyphae.

Question 3

how do flies stay immune to fungal infection?

Answer 3

• Toll is an innate PRR (that is required for fungal immunity

Question 4

what human deficiencies lead to fungal infections?

Answer 4

• Dectin 1 (a fungal pattern recognition receptor) deficiency
• CARD 9 deficiency

Question 5

how might a Dectin 1 deficiency cause lead to fungal infection?

Answer 5

• Dectin 1 deficiency leads to mucocutaneous fungal infections, for example, vulvovaginitis & onychomycosis
• Dectin 1 deficiency leads to impaired macrophage IL-6 production and binding in response to fungal infections
• Dectin 1 deficiency also leads to susceptibility to invasive aspergillosis in stem cell transplants.

Question 6

how might a CARD 9 deficiency cause lead to fungal infection?

Answer 6

• CARD-9 deficiency leads to chronic mucocutaneous candidiasis.
• this is because CARD 9 is needed for
• TNF production in response to b-glucan stimulation.
• T-cell Th17 differentiation.

Question 7

what do TLR4 polymorphisms lead to?

Answer 7

• might lead to increased risk of invasive Aspergillosis in transplantation
  (i. e. hematopoietic stem cell transplants)

Question 8

what also might cause susceptibility to invasive fungal infections and disease?

Answer 8

• there are a range of major SNPs (single nucleotide polymorphisms) which are associated with increased susceptibility to invasive fungal disease

Question 9

what are the cellular defenses to fungal infections?

Answer 9

• Neutrophilic defense (important for Aspergillus)
• macrophages

Question 10

how do neutrophils defend against fungal infections?

Answer 10

• they make neutrophil nets - this is when neutrophils throw out chromatin “nets” to capture pathogens.
• these chromatin molecules also act as danger signals and recruit effector cells to the area

Question 11

what is Fungal morphogenesis?

Answer 11

• fungi can transition between yeast, candida and hyphae forms
• this can drive modulation of dendritic cell response and can confuse the immune system

Question 12

what are innate defense mechanisms against fungal infection?

Answer 12

• Mucosal immunity

innate mucosal immunity governs fungal tolerance and resistance.

Question 13

how to treat fungal infections? x2

Answer 13

• adoptive immunotherapy
• gene therapy

Question 14

how does adoptive immunotherapy work?

Answer 14

• we generate lots of anti-fungal T cells in a sample and give it to the patient to fight the fungal infection

Question 15

how does gene therapy work?

Answer 15

• works by editing a gene to restore a function
• for example:
• restore gp91 function
• by restoring gp91 function we are able to make reactive oxidative species to fight fungal spores
• another example :
• • might be to restore the ability to restore the neutrophil net formation
• these work by restoring the initial primary immunodeficiencies

Question 16

what happens when fungal spores are inhaled?

what is the response to fungal spores?

Answer 16

• fungal spores are inhaled all the time
• the host response might be normal, ineffective or exaggerated therefore this might lead to an allergic or fungal disease

Question 17

what is the main driver of fungal allergy?

Answer 17

Aspergillus

examples = Aspergillus niger, Aspergillus fumigatus.

other supporting fungi include :

Alternaria, Cladosporium, Penicillum

Question 18

what are the important hypersensitivity fungal reactions?

Answer 18

• Types 1 3 4
• T1 – IgE-driven, involves histamine and leukotrienes, in minutes. T3 – IgG-, IgM-driven, involves complement, in 1-24 hours
• T4 – T-cell-driven, involves lymphokines, in 2-3 days.

Question 19

what is allergic Bronchopulmonary Aspergillosis:

Answer 19

a condition characterized by an exaggerated response of the immune system to the fungus Aspergillus

Question 20

what are predisposing conditions to ABPA?

Answer 20

asthma or cystic fibrosis

Question 21

what are the criteria for diagnosing ABPA?

Answer 21

• pre-disposing condition (asthma or CF)
• high baseline serum IgE
• T1 hypersensitivity skin test
• test for Aspergillus-specific IgE.

Question 22

what are the supportive criteria in diagnosing ABPA?

2 are needed for diagnosis :

Answer 22

• eosinophilia
• consistent radiologic abnormalities
• IgG Antibodies to Aspergillus fumigatus

Question 23

what are the radiologic abnormalities to ABPA?

Answer 23

• hyperdense mucus
• Dilated bronchi, thick walls.
• Ring or linear opacities
• a predilection (preference) for Upper/central lung
• Lobar collapse
• fibrotic scarring
• Proximal bronchiectasis (enlargement of parts of the airway)

Question 24

how to manage ABPA?

Answer 24

• Corticosteroids
• Itraconazole (steroid-sparing agent)
• Omalizumab = reduces sensitivity to allergens