Fungal Immunity Flashcards
What are the four main phyla of fungi and which most commonly causes human fungal infection?
Ascomycota – MAIN ONE
Basidiomycota
Chytridiomycota
Zygomycota
Give examples of how the morphogesis of fungi contributes to its ability to cause disease in the host.
- Candida albicans dimorphism between spores but they and hyphae forms which allows tissue invasion
- Cryptococcus forms a capsule to evade phagocytosis
- Aspergillus sp. are inhaled as conidia and invade tissues as hyphae
Which pattern recognition receptors in Drosophilia flies are important in detection of fungal pathogens?
TLR
Name 2 deficiencies that are associated with an increased risk of mucocutaneous candidiasis.
- Dectin 1
2. CARD 9 (downstream of Dectin 1)
Name 3 factors that are associated with increased risk of Aspergillosis in transplantation.
TLR4 – loss of function
Dectin 1
Plasminogen alleles
Which PRR is actively recruited to Aspergillus fumigatusphagolysosomes?
TLR9
What can plasminogen directly bind to?
Aspergillus fumigatus conidia
Which cells are the most important in defence against an Aspergillus fungal infection?
Neutrophils
What do neutrophils release that enable them to trap Aspergillus?
NETs
chromatin nets to capture pathogens and act outside nucleus acts as danger signals and recruit more effector cells
Describe how fungal morphogenesis governs the dendritic cell modulation of adaptive immunity.
Hyphal forms = Th2 response
Conidium = Th1 response
What cytokine therapy has been shown to enhance clearance ofinvasive fungal infection?
IFN-gamma
Describe the principles of adoptive immunotherapy for fungal infection.
Generate anti-fungal T cells, which can be cultured in large numbers and administered to the patient
Give an example of gene therapy for chronic granulomatous disorder.
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
What types of hypersensitivity reaction are associated with fungal allergies?
Type 1, 3 and 4
What are two predisposing conditions for allergic bronchopulmonary aspergillosis (ABPA)?
- Asthma
2. Cystic fibrosis
What is the obligatory criteria for ABPA?
- Total baseline serum IgE > 1000 IU/ml
- Positive immediate hypersensitivity skin test or
- Aspergillus-specific IgE
List some supportive criteria for ABPA.
- Eosinophilia > 500 cells/ul
- IgG antibodies to Aspergillus fumigatus
- Consistent radiographic abnormalities
List some radiological abnormalities/features of ABPA.
- Dilated bronchi with thick walls
- Proximal bronchiectasis
- Ring or linear opacities
- Upper or central region predilection
- Lobar collapse due to mucous impaction
- Fibrotic scarring
What might be seen in a CT scan of a patient with ABPA?
Hyper dense mucous sign
Describe the main treatment options for ABPA.
- Corticosteroids
- Itraconazole may be used as a steroid-sparing agent
- indicated if not responding to steroids or steroid dependant - Omalizumab (recombinant anti-IgE antibodies)
List three other examples of fungal allergies, including associated features of each.
- Aspergillus rhinosinusitis
- May be allergic or invasive
- Obliterated sinuses
- Treated with oral corticosteroids or surgical removal of nasal tissue - Severe asthma with fungal sensitisation
- Fungal sensitisation as a potential cause of severe asthma
- Requires exclusion of ABPA - Hypersensitivity pneumonitis (extrinsic allergic alveolitis)
- Allergy requires long-term exposure to allergen (often occupational)
What test is used to diagnose fungal allergies?
Skin prick testing
Which type of hypersensitivity is each of the previously mentioned fungal allergies?
ABPA – type 1 or 4
Asthma – type 1
Rhinitis – type 1
Hypersensitivity pneumonitis – type 4
Give specific example of mucocutaneous fungal infections due to Dectin- 1 deficiency and how this happens
Vulvovaginitis
Onchomycosis
the deficiency leads to
- impaired macrophage IL-6 production and binding in response to fungal infections
- increased susceptibility to IA (invasive aspergillosis) in stem cell transplants
What specific mucocutaneous infection does a deficiency in CARD-9 lead to?
Chronic mucocutaneous candidiasis
What is CARD-9 required for?
- TNFalpha production in response to B-glucan stimulation
2. T-cell TH17 differentiation
What do polymorphisms in TLR4 lead to?
Increased risk of IA in transplantation (e.e haematopoietic stem cell transplants)
What is Conclusion 1 in fungal immunity?
Mutations on Dectin-1, TLR4 and plasminogen confer increased susceptibility to fungal disease
What disease are plasminogen alleles linked to?
Aspergillosis
What is Fungal Morphogenesis?
fungi can transition between yeast, candida and hyphae forms (multicellular) which can drive a modulation of dendritic cell response and is bad for the immune system as it confuses it
What innate defence do we have against fungal infections?
Mucosal immunity governs fungal tolerance and resistance
What is Conclusion 2 in fungal immunity?
- Macrophages and neutrophils contribute to fungal immunity but for Aspergillus neutrophils are of a primary importance
- Dendritic cells modulate adaptive immune reponses
- Adaptive T-cell IFN gamma responses increase host immunity
- New treatments involve IFN gamma or adoptive T-cell therapy as well as gene therapy for primary immunodeficiencies
What is the primary driver in fungal allergy, and what are the supporting fungi?
primary- Aspergillus
supporting- Alternarnia, Cladosporium, Penicillum
What is Conclusion 4 in fungal allergy?
- variety of pulmonary allergies, but ABPA is best recognised
- evidence for fungal sensitisation in hypersensivity pneumonitis
- diagnosis driven by skin test, IgE and IgM in clinical relevant populations
