Host response to fungal infection Flashcards
Explain how a host response to infection with fungus?
How is fungal/yeast infection detected? Which type of PRRs are especially important in detecting fungus and what are their ligands? Which cell types are involved in this detection and which cytokines, predominantly, do these secrete in response?
The pattern recognition receptors (particularly important in fungal infections) is the C-type dectine-1 receptor, which binds to the beta-glucan ligand on the surface of the fungi.
The tissue-resident macrophages, which secretes TNF-alpha, IL-beta, IL-6 (= inflammatory cytokines) and IL-5 cytokines. They activates the local endothelium and starts an inflammatory reaction, involving the neutrophils, monocytes/macrophages, and NK cells.
Why do CARD9-deficient individuals tend to be specifically susceptible to fungal infections?
CARD9 is an intracellular molecule that is part of a complex in a signaling transduction pathway important for the fungi immune response (dectin-1 receptors). If it is impaired, then the downstream signaling will not occur/inhibited. If the signal is inhibited due to having a deficient CARD9, then there will be no response to the fungal present in the epithelium, the infection will grow and harm the host. Resulting in no recruitment of neutrophils!
Which innate cells are recruited to fungus-infected tissues and how do they contribute (functionally) to anti-fungal immunity?
Neutrophils: are likely the most important anti-fungal immune cell. It kill the fungus by phagocytosis(if small enough; yeast), NETosis, directly release of ROS, and/or secrete antimicrobial peptides. They can also ensnarl the hyphae through binding and cutting off the hyphae.
Monocytes/macrophage: the monocytes differentiate into macrophages at the site of the injury, and perform phagocytosis (if small enough) and ensnarl the hyphae. Additionally, they binds to several chemokines that are secreted in the fungal infection response.
NK cells: gets activated by DCs’ IL-23 and tissue-resident macrophages’ IL-15 cytokines. They induce the cytokines called GM-CSFs (granulocytes-monocytes co-stimulating factors) which are important in activating neutrophils to kill the fungi/yeast. They also perform degranulation by releasing IFN-gamma that engage in direct killing via NK-p30 receptor-beta-glucan complex.
Do complement proteins have a role in fungal infections? Explain.
During opsonization, the complement factor 1 (C1) binds to ab-yeast, resulting in cleavage of C3b. Thus, C3b binds to the surface of the yeast. Then the yeast-C3b complex can be phagocytosed via C3b-complement receptor interactions on phagocytes (macrophages and neutrophils).
Cleavage of C5a and C3a (inflammatory proteins) are able to track the infection and make an inflammatory gradient, which will be utilized by granulocytes (monocytes and neutrophils) to find the infection site.
What type of adaptive immunity is suitable for dealing with systemic fungus infections?
The Th1 cells, which secrete IFN-gamma and thereby activates the macrophages (with co-stimulus by the CD40/CD40L interaction).
What type of adaptive immunity is suitable for dealing with mucosal fungus infections?
The Th17 cells, gamma-delta T cells, and Innate lymphoid cells type 3 (ILC3) that secrete IL-17 and IL-22 cytokines for the activation of the epithelial cells to produce anti-microbial peptides, and B-defensins (binds to the fungi and induce killing).
Which cytokines are secreted by T cells in systemic vs. mucosal fungus infections, respectively? Describe a main function for each.
Systemic: IFN-gamma cytokines which activates the macrophages.
Mucosal: IL-17 and IL-22 that activates the epithelial cells to produce anti-microbial peptides, B-defensins that bind to the fungi and induce killing and neutrophil activation
What is the relative importance of CD8+ and CD4+ T cells in anti-fungal immunity?
CD8+ T cells might have an importance in an intracellular response to the yeast. But, they need help from other cells that can induce binding and other responses that are necessary for transporting the yeast into the cell.
CD4+ T cells respond to the fungi when it is in the extracellular space, and thus known to have larger importance in the response to fungus infection. This cells are the once that induces the killing - degranulation (secreting perforins that makes pores in the membrane) or FoxP3+ Tregs associated immunity (FoxP3 is a transcription factor to Tregs - if you have a mutation in FoxP3, then there will be a strong immunity against the fungal infection (creates a niche against fungal infections!))
How can antibodies against fungal antigens contribute to fight fungus infection?
Activate the complement system by indirect opsonization.
Direct opsonization several methods:
1: uptake by phagocytes, when talking about yeast infection (monocytes and neutrophils) 2: ensnarl hyphae and release ROS by monocytes.
3: induce the ADCC (antibody-dependent cellular cytotoxicity) that is a NK-dependent killing involving; NK cells having a CD16 receptor (type of Fc-gamma receptor) binding to the surface antibodies attached to the fungi. The Fc part of the antibody bind lightly to the CD16 receptor and make a cross-links. Then, there will be a polarisation of these bindings that results in the release of cytotoxic granzymes that makes pores in the membrane and kills the fungi.
Can you reason why HIV-infected individuals may be more prone to fungus infection compared to healthy individuals?
This is because of the dysfunctional immune system - resulting in an easier environment for the fungi to survive and cause infection. The major group that are susceptible for fungal infection are the patients with HIV!
