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    Topic review

    Fungal Host Defence

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    Submitted by: Shu Shun Li


    Humans have developed complex immune systems that defend against invading microbes, including fungal pathogens. Many highly specialized cells of the immune system share the ability to store antimicrobial compounds in membrane bound organelles that can be immediately deployed to eradicate or inhibit growth of invading pathogens. These membrane-bound organelles consist of secretory vesicles or granules, which move to the surface of the cell, where they fuse with the plasma membrane to release their contents in the process of degranulation. Lymphocytes, macrophages, neutrophils, mast cells, eosinophils, and basophils all degranulate in fungal host defence. While anti-microbial secretory vesicles are shared among different immune cell types, information about each cell type has emerged independently leading to an uncoordinated and confusing classification of granules and incomplete description of the mechanism by which they are deployed. While there are important differences, there are many similarities in granule morphology, granule content, stimulus for degranulation, granule trafficking, and release of granules against fungal pathogens.

    1. Introduction

    Lack of effective therapy is largely responsible for the high mortality [1]. The therapeutic options for fungal infections are limited and associated with toxicities, which has led to an interest in immune therapeutic approaches [2]. One such therapeutic target is granule-dependent release of antifungal molecules used in host defence.
    Immunity is a sophisticated, coordinated system consisting of highly specialized innate and adaptive immune cells that play vital roles against fungi. Both innate and adaptive immune cells are involved in fungal host defence, such as against organisms among the Ascomycota (Aspergillus fumigatus, Candida albicans), Basidiomycota (Cryptococcus neoformans), and Zygomycota (Rhizopus oryzae). NK cells, eosinophils, mast cells, neutrophils, and T cells boast intracellular membrane bound vesicles, which store compounds that can be immediately deployed for host defence. These intracellular compartments have been called “secretory vesicles”, “secretory lysosomes”, or “granules”. These organelles form when products of the trans-Golgi network are packaged into transport vesicles. Transport vesicles move the cargo to an endosome that undergoes acidification and processing of the cargo leading to formation of the secretory vesicles. Secretory vesicles contain molecules that induce fungal cell death or stasis when immune cells engage an invading pathogen.
    Immune cells not only act independently, but also work in a complex manner by releasing factors and cytokines that signal and/or prime each other to effectively clear infections. Depending on the immune cells, granules are deployed in different ways. The immune cell can bind to the pathogen and antimicrobial compounds are released directly onto the pathogen. Alternately, immune cells can bind to another host cell that contains the pathogen. In this case, the antimicrobial compounds are released in a directed way through an immunological synapse (IS) between the immune cell and the host cell containing the pathogen, leading to death of the microbe. Immune cells may not bind directly to the pathogen, but receive signals from the pathogen or surrounding cells, causing release of antimicrobial compounds in a non-directional way in the vicinity of the pathogen. Finally, granules are released onto the pathogen surface when it is trapped in an extracellular matrix made up of DNA. Granules are also recruited to phagosomes that contains the engulfed pathogen, but this intracellular pathway will not be the subject of this review.
    The mechanisms and machinery by which granules are trafficked within immune cells and released on to the pathogen vary depending on the immune cells and target pathogens. However, the immune cell subtypes share similarities in activation, signaling, and granule trafficking towards the plasma membrane.

    2. Granule Characteristics in Different Immune Cell Subsets

    Despite common features, secretory vesicles are described and classified differently for each immune cell. Granules are usually classified by size, morphology, and density using electron microscopy. If the buoyant densities of granules differ, they can be separated by centrifugation, which allows proteomic approaches to identify constituents. NK cells have three types of granules: type 1, type 2, and intermediate [3], which are grouped by their morphology (Table 1). Type 1 granules are 50–700 nm in diameter and filled with a dense core surrounded by a thin layer of vesicles [4]. Type 2 granules are 200–1000 nm in diameter and characterized by multiple vesicles and membrane whorls [3]. Intermediate granules have dense cores and multiple vesicles and are less abundant than type 2 granules [5]. Type 1 granules are fully mature while other types represent different stages of granule development [3]. Different components of the granules contain different constituents. The dense core contains cytolytic proteins, while the multivesicular domains contain lysosomal proteins (Table 2) [4]. By contrast, the granules of CD8+ T cells have not been separated by morphology. Rather, granules are characterized in one group with variable granule morphology that resembles the spectrum of granules in NK cells ranging from 100 to 1300 nm [6]. Granules in cytotoxic T cells can be separated by sucrose gradients (Table 1), which allows for separation of different proteins in granules of different buoyant density [7].
    Table 1. Granule types and contents in various immune cells.

    The entry is from 10.3390/jof7060484


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