fungal infections Flashcards
fungal infections: explain the cellular mechanisms of antifungal defence, and explain how immune status determines risk of fungal infection
what are fungi opsonised by
pentraxin-3 and MBL
5 cells involved in fungal infection
phagocytes (first line), NK cells (provide early INF-gamma), dendritic cells (influence T cell differentiation), Th1 and Th17
what allows tissue invasion in candida virulence
dimorphism
what allows cryptococcus to evade phagocytosis
capsule
how are aspergillus inhaled and invade as
inhaled as candida, invade as hyphae
how do toll receptors play an important role in phagocytosis
toll is innate pattern recognition receptor required for fungal immunity
3 human deficiencies leading to fungal infections
dectin 1, CARD-9, TLR4 polymorphism
describe what dectin 1 (fungal pattern recognition receptor) deficiency leads to
leads to mucocutaneous fungal infections, leading to impaired macrophage IL-6 production and binding in response to fungal infections, and leads to increased susceptibility to invasive aspergillosis in stem cell transplants
describe what CARD-9 deficiency leads to
leads to chronic mucocutaneous candidiasis
what is CARD-9 required for
TNF-a production in response to B-glucan stimulation, T-cell Th17 differentiation
what do TLR4 polymorphisms lead to
increased risk of invasive aspergillosis in transplantation
what are there many of which are associated with increased susceptibility to invasive fungal infections and disease
major SNPs
what 3 mutations can confer increased susceptibility to fungal disease
mutations on dectin-1, TLR4 and plasminogen
what cells are very important in fungal defence
neutrophils
describe neutrophil nets and function
neutrophils throw out chomatin nets to capture pathogens, with chromatin molecules outside nucleus acting as danger signals and recruit effector cells to area
describe fungal morphogenesis, and how this can be bad for immune response
fungi can transition between yeast, candida and hyphae forms (multicellular) and this can drive a modulation of dendritic cell response and can be bad for the immune response (as it gets confused)
what governs fungal tolerance and resistance
mucosal innate immunity
2 forms of treatment for fungal infections
adoptive immunotherapy, gene therapy
what does adoptive immunotherapy do
generates lots of antifungal T-cells in a sample, and give these to patients that need to fight a fungal infection
what happens in gene therapy to treat chronic granulomatous disorder
restore gp91 function (make reactive oxidative species to fight fungal spores) to treat chronic granulomatous disorder (restore neutrophil net formation)
what 2 white cells contribute to fungal immunity
macrophages and neutrophils (neutrophuls are primary important in aspergillus)
what do dendritic cells do
modulate adaptive immune responses
what responses augment host immunity to fungi
adaptive T-cell INF-gamma responses
2 possible new treatments for fungal infections
INF-gamma or adoptive T-cell therapy, gene therapy for primary immunodeficiencies
3 types of host response to fungal spore inhalation, and what these can lead to
normal, ineffective or exaggerated (allergy), leading to allergic or invasive fungal disease
what fungas is a primary driver of fungal allergy
Aspergillus (but other supporting fungi e.g. penicillum)
what hypersensitivity reactions are included in important fungal reactions
type 1, 3 and 4
what is a type 1 hypersensitivity reaction
IgE driven, involves histamine and leukotrienes, in minutes
what is a type 3 hypersensitivity reaction
IgG, IgM driven, involves complement, in 1-24 hours
what is a type 4 hypersensitivity reaction
T-cell driven, involves lymphokines, in 2-3 days
describe fungi allergens variation and consequence
multiple allergens per fungi, which all cross-react and cross-sensitise to post-proteins, causing an autoimmune response
describe pathophysiology of allergic bronchopulmonary aspergillosis
inhale spores -> abnormalities in dendritic cells so Th17 responses in lungs -> B-cells produce IgE -> mast cell granulation and eosinophilia
criteria for allergic bronchopulmonary aspergillosis diagnosis
predisposing condition (asthma, CF), obligatory criteria (high baseline IgE, positive type 1 hypersensitivity skin test or aspergillus specific IgE), supportive criteria (eosinophilia, IgG to aspergillus, consistent radiological abnormalities)
describe radiological abnormalities which can be seen in allergic bronchopulmonary aspergillosis
hyper-dense mucus, dilated bronchi with thick walls, ring/linear opacities, upper/central predilection, proximal bronchiectasis, lobar collapse, fibrotic scarring
3 managements of allergic bronchopulmonary aspergillosis
corticosteroids, itraconazole (steroid-sparing agent; if not responding to steroids or if steroid-dependency), omalizumab (recombinant IgE monoclonal antibodies)
what is the best pulmonary allergy to fungi
allergic bronchopulmonary aspergillosis
