Fungal Immunity Flashcards
what are the four groups of fungi?
Zygomycota
Ascomycota
Basidiomycota
Deuteromycota
what are fungi opsonised by to enable phagocytosis?
pentraxin-3 and mannose-binding lectin (MBL)
what cells are involved in the immune response to fungi?
o Phagocytes – first line of defence. o NK cells – provide early IFN-gamma. nb immune cells produce type 2 IFNs o Dendritic cells – influence T-cell differentiation. o Th1 and Th17 cells.
what enables the virulence of candida?
dimorphism allows tissue invasion
candida albicans causes mucosal infections
what enables the virulence of cryptococcus?
capsule evades phagocytosis
causes meningitis in HIV patients
what enables the virulence of aspergillus?
inhaled as conidia, invade as hyphae
deficiencies and polymorphisms in which proteins can lead to fungal infections?
- dectin 1 (PRR-impaired macrophage IL-6 production)
- CARD9 (an adaptor molecule needed for TNF-alpha production and Th17 differentiation. Both needed to surmount macrophages action.)
- TLR4
- SNPs
how does Dectin 1 def lead to fungal infection?
- dectin 1 is a fungal PRR
- def. leads to impaired macrophage IL-6 production and binding in response to infection
- leads to mucocutaneous fungal infections – e.g. vulvovaginitis & onychomycosis
- increased susceptibility to invasive aspergillosis in stem cell transplants
how does CARD9 deficiency lead to fungal infection?
- CARD-9 is a downstream to dectin 1, an adapter protein required for
TNFa production in response to beta-glucan stimulation. - enables T-cell Th17 differentiation
- leads to chronic mucocutaneous candidiasis
what is the associated increased risk with TLR4 polymorphisms?
increased risk of Invasive Aspergillosis (IA) in transplantation (i.e. haematopoietic stem cell transplants).
what is the associated increased risk with SNPs?
increased susceptibility to invasive fungal infections and disease
examples of SNPS: CXCL10, IL1-R, IL-23R, TLR-2/4/6/9.
what mutations confer increased susceptibility to fungal disease?
Dectin-1, TLR4 and plasminogen
what is the important immune cell in fungal defence?
neutrophils
macrophages
monocytes
neutrophils particularly for aspergillius
how do neutrophils neutralise pathogens?
- neutrophils throw out chromatin “nets” to capture pathogens.
- chromatin molecules outside the nucleus act as “danger signals” and recruit’s effector cells to the area as well.
how does fungal morphogenesis impact the dendrite cell response?
- fungi can transition between yeast, candida and hyphae forms (unicellular to multicellular)
- this can drive a modulation of Dendritic cell response
- this can be bad for the immune response (as it gets confused)
- mucosal immunity governs fungal tolerance and resistance
how can fungal infections be treated?
o Adoptive (T-cell) immunotherapy
o Gene therapy
- IFN gamma
what is adoptive immunotherapy?
generate lots of antifungal T-cells in a sample and then give these to the patients that need to fight a fungal infection.
what is gene therapy?
e.g. restore gp91 function (make reactive oxidative species to fight fungal spores) to treat chronic granulomatous disorder.
E.g. restore neutrophil NET formation.
what cells modulate adaptive immune responses?
dendritic cells
Adaptive T-cell INF-gamma responses augment host immunity to fungi.
error in dendritic cell response leads to ABPA
what is a primary driver of fungal allergy?
o Aspergilli
– Aspergillus niger, Aspergillus fumigatus –> lung irritation
o Other supporting fungi
– Alternaria, Cladosporium, Penicillum
what hypersensitivity reactions are involved in fungal reactions?
1,3,4
type 1 hypersensitivity reaction
IgE-driven, involves histamine and leukotrienes, in minutes
type 2 hypersensitivity reaction
IgG-, IgM-driven, involves complement, in 1-24 hours
type 3 hypersensitivity reaction
IgG-, IgM-driven, involves immune complexes, in 1-24 hours
- deposit in endothelium
- cause compliment activation
type 4 hypersensitivity reaction
T-cell-driven, involves lymphokines, in 2-3 days.
what is the criteria for diagnosis of Allergic Bronchopulmonary Aspergillosis (ABPA)?
o Predisposing condition –
asthma or cystic fibrosis.
o Obligatory criteria –
- high baseline serum IgE
- +ve T1 hypersensitivity (immediate response) skin test
- Aspergillus-specific IgE
o Supportive criteria (more than 2) –
- eosinophilia
- IgG AB to Aspergillus fumigatus
- consistent radiologic abnormalities.
what are the radiological abnormalities seen in ABPA?
- Dilated bronchi, thick walls.
- Upper/central predilection.
- Lobar collapse.
- Ring or linear opacities
- Proximal bronchiectasis.
- Fibrotic scarring.
what is the damage response framework?
outcome dependent on host-microbe interaction:
an integrated theory of microbial pathogenesis that puts forth the view that microbial pathogenesis reflects the outcome of an interaction between a host and a microbe, with each entity contributing to the nature of the outcome, which in turn depends on the amount of host damage that results from the host-microbe interaction.
what leads to ABPA?
abnormality in dendritic cell response
how is ABPA managed?
o Corticosteroids.
o Itraconazole (steroid-sparing agent)
- Indicated if not responding to steroids or if steroid-dependency.
o Omalizumab
– recombinant IgE monoclonal ABs
which are the important fungi causing infection?
- candida
- aspergillus
- crytococcus
who are the most vulnerable to fungal infection?
- immune compromised
e. g. cancer patients - AIDS patients
- transplant recipients
which fungal infection is associated with AIDS?
pneumocystis pneumonia (pneumocystis jirovecii)
why are haematological cancer patients vulnerable to fungal infection?
prolonged and profound neutropenia (low neutrophil count)
after treatment with highly cytotoxic chemotherapy for haematological malignancies and recipients of haematopoietic stem cell transplantation (HSCT)
puts them at risk
why does the fungal morphotype determine the host response?
yeasts and spores are often effectively phagocytosed
the larger size of hyphae precludes effective ingestion.
which are the fundamental antigen fungal effector cells?
Neutrophils, macrophages and monocytes
what are some fungal ligands that can be recognised by immune cells?
1,3 β-glucans
mannans
chitin
what effect do fungi have on complement?
- Fungi are potent activators of the complement system, resulting in opsonisation due to deposition of C3b on the fungal surface and recruitment of inflammatory cells
- C3a and C5a are generated
- fungi are resistant to complement-mediated lysis, presumably due to their thick cell wall
- Fungi can activate the classical, alternative, and lectin complement pathways
which receptor is important in mediating the immune response to fungal infection?
Toll-like receptor
which rare genetic disease leaves people vulnerable to fungal infection?
Chronic granulomatous disease (CGD)
- have defects in the enzyme NADPH oxidase
- therefore their neutrophils are unable to kill ingested pathogens
- vulnerable to aspergillus species
neutrophils are important
who are the highest risk of infection?
those with prolonged, profound neutropenia after treatment with highly cytotoxic chemotherapy for haematological malignancies
recipients of haematopoietic stem cell transplantations
how does hyphae size affect phagocytosis ?
the larger the harder
how are fungal cell wall detected by innate immunity ?
pattern recognition receptors
e.g. dectin-1 , CD5, mannose receptor
the fungal cell wall is the main target for treatment therapies
what are some fungal PAMPs/ligands?
1,3 beta glucans
mannans
chitin
why are fungi resistant to complement mediated lysis despite triggering the complement system?
thick cell wall
they activate the classical, alternative and lectin complement pathways
when is the lectin complement pathway activated by fungi?
recognition of exposed mannans by mannose-binding lectin (MBL)
triggers MBL-associated serine proteases
what genetic defect is seen in chronic granulomatous disease?
- defect in NAPDH oxidase
- neutrophil underable to kill ingested pathogens
what Fingal infection are people with chronic granulomatous disease most susceptible to?
aspergillus species (explained by low neutrophil count)
what T cells are predominate in the protective response to fungal infections?
Th1 Cd4+
