Rob's Fungal Immunity Flashcards
Which fungi classes cause disease in humans
3 phyla causing disease in humans Zygomycota Basidiomycota `Ascomycota (bottom 2 more closely related)
Give an example of ascomycota
Candida and Aspergillus
Give examples of basidiomycota
Mushrooms(cryptococci)
List Fungi causing infections
Aspergillus (ascomycota) Cryptococcus (basidiomycota) Candida albicans (ascomycota)
How can aspergillus cause problems
Have spores called conidium.Normally fine, most people inhale every day Only a problem if you have no neutrophils Can germinate (leading to fungal ball) and cause bleeding in LUNGS
How can Cryptococcus neoformans cause disease
Mushroom group (microscopic) .Fimbrae that allow it to adhere to surfaces .Commonest cause of death in HIV patients (subsaharan Africa) .Inhaled through lungs but can disseminate to brain if lack of CD4+ T cells. Leads to cryptococcal meningitis. Can then develop cryptococcomas (fungal ball) , and stroke like symptoms.
What is cryptococcoma
Ball of fungus which has germinated. CNS (cryptococcus neoformans)
How can candida albicans cause disease
Candida is commensal on skin and gut But in immunocompromised/catheterised, can develop invasive infeection. Can get into the back of the eye creates mass =candida endophthalmitis, for example
Outline cellular immunity to fungal infection
Innate immune system very important. Loss of neutrophils is a key risk factors .Most fungi encountered at mucosal surface (in gut, yeast or on lungs as moulds). Opsonisation, phagocytes and complemet all important. Dendritic cells present antigen to T cells Can lead to Th1, Th2 and Th17 responses(these then determine innate response-circle).
Why are NK cells important in cellular immunity to fungal infection
They produce IFN-g which primes macrophage to deal with fungus
Outline how fungi change shape Candida, cryptococcus and aspergillus
Can start as unicellular organisms then become mutlicellular ▪Candidal dimorphism (starts of as budding yeast but when it is involved in invasioive infections changes into hyphal forms, which are muticellular filamentoius structurees) allows tissue invasion ▪Crytpococcus divides in the host as a yeast. Forms a capsule to evade phagocytosis ▪Aspergillus species inhaled as conidia, invade tissues as hyphae
How can fungi be sensed
Toll like receptors (innate receptor). Losing the toll systems put you at high risk of fungal disease
What are c-type lectins
Part of immunoglobulin super family.Detect carbohydrate on fungal cell wall. Important for phagocytosis of fungi (TLR cannot do it alone, need c -type lectins).
What receptors are important in fungal infection
TLR, c-type lectins and scavenger receptors
T/F scavenger receptors normally phagocytose non-inflammatory materials
T
What deficiencies could result in chronic mucocutaneous candidasis
c-type lectin is really importnat in fungal immunity. Mutations and thus deficiency of Dectin 1[Dectin 1 (a c-type lectin). It binds candida. Without dectin 1 ,cannot produce IL-6 or bind], and CARD9, a protein in the downstream signalling pathays for many c-type lectins, can result in chronic mucocutaneous candidiasis.
What is worse, dectin 1 or CARD9 deficiency
CARD9, because this is the signalling molecule for the actiation of many receptors
Why is CARD9 required in fungal immunity
Functional Card9 is Required for TNFα Production in Response to βGlucan ,and is also Required for T cell Th17 Differentiation in Humans. (SHOWS THAT DEFECTIVE INNATE RECEPTORS MEANS THAT ADAPTIVE IMMUNE SYSTEM CAN THEN NOT BE TRAINED TO DEAL WITH THE FUNGI
Why is Th17 response importnat in fungal disease
Mucosal protection .But in CARD9 deficiency, Th17 does not differentiate properly (showing that innate immune reponse interacts with adaptive one) and you get chornic mucocutaneous candidasis
Explain why fungal infections are important in stem cell transplantation, give an example of one that is important.
Apergillosis (stem cell transplantation occurs in leukaemia. All your own bone marrow wiped out with txic drugs. Give someone else’s bone marrow. That bone marrow will act as your bone marrow, creating your red and white cells. But it will also attack your own immune system to destroy all of the bone marrow cancer) But during that period of the transplanted bone marrow killing your bone marrow and then producing new cells, there are less neutrophils and less innate immunity, and these patents very susceptible to fungal infection including aspergillosus .TLR4 polymophoisms can alter risk of pulmonary aspergillosis in transpantation
What proteins are important in risk of invasive aspergillosis in stem cell transpantation
Dectin 1 and TLR4
Mutations in which haemostasis related protein increases susceptibility to fungal disease
Plasminogen (as well as dectin1, TLR4)
Why will fungal immunogenics be important
E.g in transplant patients you can look at their TLR4 phenotype and see if this is going to place them at a risk of a certain infection and then give prophylactic medication (ABs)
What are important innate immunity cells in fungus infection
Both macrophages and neutrophils contribute to fungal immunity However for Aspergillus neutrophils are of primary importance
What happens if you took neutrophil away from lung and put aspergillus there
It would grow as it would in a test tube Basically, without neutrophils aspergillus will grow so easily and body doesn’t really do anything with it
Outline one way in which neutrophils deal with fungi
Neutrophl extracellular nets DNA released by dead neutrophils and this binds the aspergillus (in this cause aspergillus fumigatus) and is very sticky This is the reason for very sticky mucus in these sorts of infections
Other function of neutrophil DNA other than coding for proteins
Neutrophil extracellular trap And, when released from cells, acts as a DAMP (along with histones, actin etc.)
When do Th1 responses occur and when do Th2 responses occur generally
Th2 is development of allergic response i.e. eosinophil and mast cell degranulation Th2 is promoted by worms and parisitic infections because they are too big to phagocytose, so Th1 response isn’t approrpiate Th1 response occur against intracellular parasites such as bacteria and viruses which can be phagocytosed
What are the important cytokines for Th1 and Th2
Th1: TNF-a, IFN-g and IL-6 and IL-12 stimulates macropahges Th2: IL4/IL-10 for eosinophil and mast cells
Outline the T helper response to fungi
DEPENDS on fungal morphogenesis. At first, the fungi might be in the yeast form but then can take different forms (hyphae form/capsule) Dendritic cells take up antigen. For the yeast form of candida, leads to Th1 (as it’s smaller and can be phagocytosed) In the hyphae form of candidam there is Th2 response as now the yeast is filamentous and big so requires allergic response not phagocytic Same for aspergillus conida (Th1) vs aspergillus hyphae (Th2)
What is the relevance of both Th1 and Th2 responses to fungal infection
They have both invasive infectious disease AND drive allergy including asthma
Outline novel methods of treating fungal disease based on immunotherapy and gene editing (not necessary just incase you stressed)
IMMUNOTHERAPY. T cell adoptive therapy. In the stem cell transplant example, we said that patients were susceptible to aspergillus (and candida) after stem cell transplant. After taking stem cells from the donor, you can select for T cells with specific fungus binding receptors, and give these to the patient if they get fungal infection after the HSC transplant has occurred. Gene editing: There is mutation in NADPH oxidase which is present on plasma membrane of phagosome to generate reactive oxidants in the RESPIRATORY BURST to kill organisms phagocytosed by neutrophils for example. A boy who had mutation in this protein had chronic granulomatous disorder. They took out his bone marrow and gene edited all of the cells using a virus to correct the mutation. Then then killed all his other bone marrow cells that weren’t gene edited, re-infused the edited bone marrow cells which now contain functional NADH oxidase. There was also a restoration of neutrophil NET formation :)
What is the importance of T cell interferon gamma
Adaptive T cell interferon-gamma responses augment host immunity to fungi
For candida and aspergillus, neutrophls are importnat. What about for cryptococcus
Cryptococcus more in HIV patients. CD4+ T cells more important
Give examples of aspergillu environmental organisms
Aspergillus niger Aspergillus fumigatus Inhaled leading to fungal allergic airway disease. Spores get into lungs really easily
T/F people with asthma due to fungi like aspergillus are getting it due to immunosupression
F they are getting it because of an exaggerated immune response
Outline a type of fungal disease fo each category of hypersensitivity reacton
Type 1 (IgE/histamine mediated) –> allergic rhinitis, allergic asthma, ABPA Type 2 –> unknown Type III–> hypersensitivity pneumoniits/aspergilloma Type IV –> hypersensitivity pneumonitis
T/f there is just one allergen in fungi that causes hypersensitive response
F
Outline why fungal allergens are confusing for immune system
Cross reactivtiy between candida allegens in the gut and breathed in allergens in the lung (immune system doesn’t know which it is responding to) And Because they are eukaryotic, some allergens from fngi have promoted autoimmue response against self antigens in the lung
What leads to allergic and what leads to invasive fungal disease
Wheter host response is ineffective or exaggerated
What type of hypersensitivity reactions are occurring in fungal infections
I, III and IV
What is the primary driver of allergic fungal disease
Aspergillus
What is ABPA
Allergic bronchopulmonary aspergillosus which causes IgE response and is a form of bronchiectasis High eosinophil levels in peripheral blood Loads of mucus Overexagerated immune response
Which conditions presispose to ABPA
Asthma or cystic fibrosis
Radiological features of ABPA
• Dilated bronchi with thick walls • Ring or linear opacities • Upper or central region predeliction • Proximal bronchiectasis • Lobar collapse due to mucous impaction (hyper dense mucus) • Fibrotic scarring
What happens to size of airways with ABPA
DILATION (this is bronchiectasis) Bronchiectasis is a long-term condition where the airways of the lungs become abnormally widened, leading to a build-up of excess mucus that can make the lungs more vulnerable to infection Because of mucus plugging
Management of ABPA
Corticosteroids Itraconazole for steroid sparing effect (a triazole) Recombinant IgE monoclonal antibodies
What is an anti-IgE antibody
Omalizumab
What is hypersensitivity pneumonitis
Fibrotic lung disease Evidence for fungal sensitisation
What is diagnosis of fungal hypersensitivity driven by
Diagnosis driven by skin test, IgE and IgM in clinical relevant populations
