Rob's Fungal Immunity COPY COPY Flashcards
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 :)
