Host cell membrane microdomains and fungal infection

Abstract

Lipid microdomains or lipid rafts are dynamic and tightly ordered regions of the plasma membrane. In mammalian cells, they are enriched in cholesterol, glycosphingolipids, Glycosylphosphatidylinositol-anchored and signalling-related proteins. Several studies have suggested that mammalian pattern recognition receptors are concentrated or recruited to lipid domains during host-pathogen association to enhance the effectiveness of host effector processes. However, pathogens have also evolved strategies to exploit these domains to invade cells and survive. In fungal organisms, a complex cell wall network usually mediates the first contact with the host cells. This cell wall may contain virulence factors that interfere with the host membrane microdomains dynamics, potentially impacting the infection outcome. Indeed, the microdomain disruption can dampen fungus-host cell adhesion, phagocytosis and cellular immune responses. Here, we provide an overview of regulatory strategies employed by pathogenic fungi to engage with and potentially subvert the lipid microdomains of host cells. Take Away• Lipid microdomains are ordered regions of the plasma membrane enriched in cholesterol, glycosphingolipids (GSL), GPI-anchored and signalling-related proteins.• Pathogen recognition by host immune cells can involve lipid microdomain participation. During this process, these domains can coalesce in larger complexes recruiting receptors and signalling proteins, significantly increasing their signalling abilities.• The antifungal innate immune response is mediated by the engagement of pathogen-associated molecular patterns to pattern recognition receptors (PRRs) at the plasma membrane of innate immune cells. Lipid microdomains can concentrate or recruit PRRs during host cell-fungi association through a multi-interactive mechanism. This association can enhance the effectiveness of host effector processes. However, virulence factors at the fungal cell surface and extracellular vesicles can re-assembly these domains, compromising the downstream signalling and favouring the disease development.• Lipid microdomains are therefore very attractive targets for novel drugs to combat fungal infections.

Microbial lectome versus host glycolipidome: How pathogens exploit glycosphingolipids to invade, dupe or kill

“…Hahn et al (2003) found that blocking LacCer using a specific anti-LacCer antibody markedly decreased the release of macrophage inflammatory protein (MIP-2). Similar results were obtained using GSLs inhibitors (N-butyldeoxyno jirimycin and d-threo-1-phenyl-2-decanoylamino-3-morpholino-1propanol-HCl), suggesting that LacCer may also play a significant role in inducing β-glucan-induced inflammatory signaling of P. jirovecii pathogenesis (Hahn et al, 2003;Souza et al, 2021).…”

“…Histoplasma capsulatum is a dimorphic fungus responsible for histoplasmosis, one of the most frequently occurring invasive fungal pulmonary infections (Gnat et al, 2021;Souza et al, 2021). This pathogen produces a cell surface 60 kDa heat shock protein (HSP60) which recognizes complement receptor 3 (CR3) on macrophages, leading to H. capsulatum HSP60 internalization.…”

“…The interactions between immune cells and H. capsulatum depend on lipid microdomains on the cell surface, and the presence of sialylated GSLs, such as GM1, which is required for recruitment of CR3 into the cell membrane (Lin et al, 2010). Impaired adhesion in the absence GM1 may be a co-receptor in the initial steps of host-H. capsulatum interactions (Guimarães et al, 2019;Souza et al, 2021). In addition, LacCer, a key GSL in Src family tyrosine kinase Lyn-dependent signaling pathway, plays a crucial role in H. capsulatum pathogenesis by regulating cytoskeleton remodeling (Nakayama et al, 2013).…”

Pathogenicity & virulence of Histoplasma capsulatum - A multifaceted organism adapted to intracellular environments

“…Recently, our group demonstrated the relationship between the organization of lipid microdomains (LD) and the process of H. capsulatum yeast internalization by macrophages [ 102 ]. LDs are dynamic and highly organized regions of the plasma membrane that contain or recruit pattern recognition receptors during pathogen–host interaction [ 103 ]. LD favor recruitment and clustering of receptors and co-receptors impacting ligand recognition and signaling transmission between pathogens and host cells [ 104 ].…”

“…Finally, CD18 mobilization to lipid microdomains was reduced in macrophages from B4galnt1 −/− . It appears that LD assembly is relevant for a correct and stable recognition of H. capsulatum by macrophages [ 102 , 103 ]. The absence of LD components apparently delays the integrin mobility, modifying the adhesion kinetic and consequently, the dynamic of fungal internalization, a process in which, the involvement of lipid rafts and associated protein-lipid diffusion has been implied [ 105 ].…”