Abstract
Candida spp. are an important source of systemic and mucosal infections in immune compromised populations. However, drug resistance or toxicity has put limits on the efficacy of current antifungals. The C. albicans cell wall is considered a good therapeutic target due to its roles in viability and fungal pathogenicity. One potential method for improving antifungal strategies could be to enhance the detection of fungal cell wall antigens by host immune cells. ß(1,3)-glucan, which is an important component of fungal cell walls, is a highly immunogenic epitope. Consequently, multiple host pattern recognition receptors, such as dectin-1, complement receptor 3 (CR3), and the ephrin type A receptor A (EphA2) are capable of recognizing exposed (unmasked) ß(1,3)-glucan moieties on the cell surface to initiate an anti-fungal immune response. However, ß(1,3)-glucan is normally covered (masked) by a layer of glycosylated proteins on the outer surface of the cell wall, hiding it from immune detection. In order to better understand possible mechanisms of unmasking ß(1,3)-glucan, we must develop a deeper comprehension of the pathways driving this phenotype. In this review, we describe the medical importance of ß(1,3)-glucan exposure in anti-fungal immunity, and highlight environmental stimuli and stressors encountered within the host that are capable of inducing changes in the levels of surface exposed ß(1,3)-glucan. Furthermore, particular focus is placed on how signal transduction cascades regulate changes in ß(1,3)-glucan exposure, as understanding the role that these pathways have in mediating this phenotype will be critical for future therapeutic development.
Highlights
Candida species are the most common human fungal pathogens and are ranked as the fourth most frequent cause of hospital-acquired bloodstream infections, with up to 40% mortality in epidemiological studies (Wisplinghoff et al, 2004; Horn et al, 2009)
As a central component of the cell wall, and as a consequence of the pro-inflammatory nature of this epitope, ß(1,3)-glucan exposure is highly regulated to ensure successful host immune system evasion during infection. This is highlighted by virulence defects during systemic infection with mutants that have increased ß(1,3)glucan unmasking, such as deletions in the phosphatidylserine synthase gene CHO1 (Chen et al, 2010), the glycosyltransferase gene KRE5 (Herrero et al, 2004), the yeast cell wall protein YWP1 (Yang et al, 2020) and the exo-1,3 and endo-1,3-glucanses XOG1 and ENG1, respectively (Childers et al, 2020; Yang et al, 2020)
With respect to iron limitation, which induced the strongest change in ß(1,3)-glucan exposure levels of these metals, the observed masking was associated with decreased phagocytosis by bone marrow derived macrophages (BMDMs) and reduced secretion of the pro-inflammatory cytokines TNFα, IL-6, and MIP-s1α by human peripheral blood mononuclear cells (hPBMCs)
Summary
Candida species are the most common human fungal pathogens and are ranked as the fourth most frequent cause of hospital-acquired bloodstream infections, with up to 40% mortality in epidemiological studies (Wisplinghoff et al, 2004; Horn et al, 2009). The majority of life-threatening fungal infections are opportunistic in nature, and a novel approach that may be necessary to complement current antifungals will be to simultaneously improve host immune efficacy This can include cytokine therapy and other adjunctive therapeutic approaches (Casadevall and Pirofski, 2001; Netea et al, 2008). As a central component of the cell wall, and as a consequence of the pro-inflammatory nature of this epitope, ß(1,3)-glucan exposure (referred to as unmasking) is highly regulated to ensure successful host immune system evasion during infection This is highlighted by virulence defects during systemic infection with mutants that have increased ß(1,3)glucan unmasking, such as deletions in the phosphatidylserine synthase gene CHO1 (Chen et al, 2010), the glycosyltransferase gene KRE5 (Herrero et al, 2004), the yeast cell wall protein YWP1 (Yang et al, 2020) and the exo-1,3 and endo-1,3-glucanses XOG1 and ENG1, respectively (Childers et al, 2020; Yang et al, 2020). Cell wall architecture is an important mediator in facilitating the dectin-1 immune response
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