Dynamic Fungal Cell Wall Architecture in Stress Adaptation and Immune Evasion

Abstract

Deadly infections from opportunistic fungi have risen in frequency, largely because of the at-risk immunocompromised population created by advances in modern medicine and the HIV/AIDS pandemic. This review focuses on dynamics of the fungal polysaccharide cell wall, which plays an outsized role in fungal pathogenesis and therapy because it acts as both an environmental barrier and as the major interface with the host immune system. Human fungal pathogens use architectural strategies to mask epitopes from the host and prevent immune surveillance, and recent work elucidates how biotic and abiotic stresses present during infection can either block or enhance masking. The signaling components implicated in regulating fungal immune recognition can teach us how cell wall dynamics are controlled, and represent potential targets for interventions designed to boost or dampen immunity.

Keywords: cell wall; evasion; fungi; glucan; innate immunity.

Figure 1. Stress-triggered cell wall remodeling affects immune recognition through epitope (un)masking

Environmental stresses, including pH, hypoxia, altered carbon sources, and immune attack can trigger fungal response pathways that remodel the cell wall and alter PAMP availability. The roles of specific signaling proteins and pathways are detailed in Fig. 3 and Fig. 4. The effects on the cell wall lead to enhanced exposure (in the cases of low pH or immune attack) or increased masking of cell wall β-glucan and chitin (in the case of environmental lactate). The roles of specific cell wall remodeling enzymes in response to immune attack is detailed in Fig. 4. Changes in the availability of these PAMPs alter immune recognition and responses.

Figure 2. Fungi differentiate to change their function and form, and their cell wall architecture is designed to mask some epitopes from immune recognition

The simplified cell wall architectures of select human pathogenic fungi are depicted schematically (adapted from [47]). The outer cell wall layers (shown in red) of Candida, Aspergillus, Histoplasma and Cryptococcus forms are generally capable of preventing pattern recognition receptors from binding to ligands that are buried within inner layers of the cell wall (shown in gray to indicate masking). The polysaccharide and protein components of the outer layers differ among pathogenic fungi. In some cases, such as A. fumigatus swollen conidia, rapid growth leads to the temporary unmasking of underlying epitopes, but in most cases during in vitro growth only small proportions of the cell wall are sufficiently unstructured to allow binding of immune receptors to inner polysaccharide molecules (shown in green to indicate surface exposure). Morphological transitions (indicated by curved arrows) that occur during infection by Aspergillus, Histoplasma and Cryptococcus are associated with cell wall changes that affect epitope exposure. Not much is known about the cell wall architecture of H. capsulatum or C. neoformans spores, so the layering is still unknown and these schematics are drawn in faded colors.

Figure 3. Abiotic environmental conditions can either enhance PAMP exposure or lead to greater masking

(A) Schematic outlining how acidic pH and lactate signal C. albicans to alter availability of β-glucan and chitin for immune recognition, based on [24] and [19]. (B) C. albicanscells exposed to glucose or lactate were stained for exposure of β-glucan (Fc-Dectin-1, green), mannan (Concanavalin A, red) and chitin (wheat germ agglutinin, blue). Image generated by Gabriela Avelar, Aberdeen Fungal Group. (C) C. albicans cells exposed to growth media buffered to pH 6 or pH 4 were stained for exposure of β-glucan (Fc-Dectin1, green) chitin (wheat germ agglutinin, cyan) and total chitin (Calcofluor white, magenta). Arrowheads indicate points of β-glucan exposure.

Figure 4. Immune-mediated attack of fungal hyphae triggers epitope exposure

(A) Neutrophil attack through extracellular trap (NET) formation, including activity of phagocyte oxidase, myeloperoxidase (MPO), and reactive oxygen species (ROS) causes cell wall protein damage and provokes stress responses. (B) Cell wall remodeling triggered by NET attack includes localized Chs3p-mediated chitin deposition and enhanced β-glucan exposure. Unmasking of β-glucan is reduced or abolished in the absence of Hog1p or Chs3p activity. The Phr1p transglycosyltransferase localizes to sites of neutrophil attack and may actively remodel β-glucan in the cell wall. Indirect effects are indicated by lines with dotted outlines. Schematic based on [22].