1. Immunity to fungal infections Flashcards
What causes pneumocystis pneumonia (PCP) and what is it associated with?
- Pneumocystis jirovecii
* Associated with AIDS
What patients are at particular high risk of fungal infections?
- Patients with prolonged and profound neutropenia after treatment with highly cytotoxic chemotherapy for haematological malignancies
- Recipients of haematopoietic stem cell transplantation
How can fungal morphology affect the host response?
Larger sized (e.g. hyphae) preclude effective ingestion compared to yeasts and spores
Which cells have a role in linking innate and adaptive response to a range of pathogenic fungi?
Dendritic cells
Which cell type predominates in protective responses to various fungal infections, and which cytokine is important in this response?
- Th1 type CD4+ T cell
* interferon-γ
Is innate or adaptive immunity more important in fungal infection?
Innate
Outline the cellular immune response to fungal infection
- Opsonisation by pentraxin 3 and mannose-binding lectin
- Phagocytes - first line of defence
- NK cells - provide interferon-γ
• Failure of innate immunity leads to adaptive responses:
- dendritic cells influence T cell differentiation
- Th1 and Th17 play a role
What is Candidal dimorphism?
Grows in yeast and hyphal forms - allows tissue invasion
In what form does Aspergillus invade tissues?
Hyphae
How are fungal cells detected?
- Cell walls sensed by pattern recognition receptors
* Toll like receptors
How are Toll like receptors (TLR) important in fungal immunity and complement?
- Sense fungal components
- Expressed on sentinel cells (macrophages and dendritic cells)
- Activate immune cell responses - recruiting neutrophils and monocytes using cytokines, chemokines etc.
- Complement activated - opsonisation due to deposition of C3b on fungal surface
- Recruitment of inflammatory cells due to C3a and C5a generation
Which complement pathways can fungi activate?
Classical, alternative and lectin
What complement activity are fungi resistant to?
Complement-mediated lysis (due to thick cell wall)
Which antibodies in normal human serum are involved in a fungal cell response and how?
- Antibodies to fungal cell wall components
- Particularly mannans - can initiate classical pathway activation upon binding
- May directly opsonise fungi for recognition by phagocytic Fc receptors (FcRs)
When does activation of the lectin pathway occur (with reference to mannans)?
When recognition of exposed mannans by mannose-binding lectin (MBL) triggers MBL-associated serine proteases
Summarise Human Dectin 1 Deficiency
- HD1 is normally important in the phagocytosis of Candida and the immunity to chronic mucocutaneous candidiasis
- Loss of function mutation - mendelian susceptibility to chronic mucocutaneous cadidiasis
- Homozygous mutation - reduced inflammatory response via IL-6
Summarise Human CARD9 deficiency
- CARD9 is an adaptor molecule downstream of C-type lectins
- Required for TNF-alpha production in response to beta-glucan stimulation
- Required for T cell Th17 differentiation
- CARD9 deficiency patients are susceptible to mucosal and invasive infection
- Chronic mucocutaneous cadidiasis
What can the TLR4 loss of function mutation cause?
Increased risk of aspergillosis
How can we predict which fungi someone will be most susceptible to?
Finding a patient’s immunogenomics
Which immune cells are of primary importance for aspergillus?
Neutrophils
Are macrophage-depleted mice susceptible to aspergillus fumigatus infection?
No, neutrophils are important
What different responses are generated if you feed dendritic cells with unicellular fungal forms (e.g. yeast) or multicellular (hyphal) forms?
- Unicellular - Th1 adaptive response, typified by IFN-γ
* Multicellular - Th2 adaptive response, typified by IL-4 and IL-10
What pathogens is Th2 normally associated with?
Worms, but also deals with hyphae as they are too large to be phagocytosed
What is Th1 normally mediated by?
Neutrophils and macrophages - resulting in phagocytosis
