Maintaining phagosome integrity during fungal infection: do or die?

Abstract

Professional phagocytes represent a critical node in innate immunity and tissue homeostasis through their specialized ability to eat, drink, and digest material from the extracellular milieu. The degradative and microbicidal functions of phagocytes rely on the fusion of lysosomes with endosomal compartments such as phagosomes, resulting in the digestion and recycling of internalized prey and debris. Despite these efforts, several particularly dangerous infections result from a class of tenacious pathogens that resist digestion, often surviving and even proliferating within the confines of the phagosomal membrane. One such example, Candida albicans, is a commensal polymorphic fungus that colonizes ~50% of the population and can cause life-threatening infections in immunocompromised patients. Not only can C. albicans survive within phagosomes, but its ingestion by macropahges triggers a yeast-to-hyphal transition promoting rapid intraphagosomal growth (several microns per hour) while imposing a substantial mechanical burden on the phagosomal membrane surrounding the fungus. Preservation of membrane integrity is essential to maintain the hostile internal environment of the phagosome, a functionality of degradative enzymes and oxidative stress. Yet, biological membranes such as phagosomes have a limited capacity to stretch. Using C. albicans as a model intracellular pathogen, our recent work reveals a mechanism by which phagosomes respond to intraphagosomal growth of pathogens by expanding their surface area, and as a result, maintain the integrity of the phagosomal membrane. We hypothesized that this expansion would be facilitated by the delivery and fusion of membrane from extraneous sources with the phagosome. Consistently, macrophages respond to the yeast-to-hyphal transition through a stretch-induced release of phagosomal calcium, leading to recruitment and insertion of lysosomes that accommodate the expansion of the phagolysosome and preserve its integrity. Below, we discuss this calcium-dependent mechanism of lysosome insertion as a means of avoiding phagosomal rupture. Further, we examine the implications of membrane integrity on the delicate balance between the host and pathogen by focusing on fungal stress responses, nutrient acquisition, inflammasome activation, and cell death.

Non-canonical activation of IRE1α duringCandida albicansinfection enhances macrophage fungicidal activity

“…7B). As the phagolysosomal environment restricts C. albicans hyphal growth 66 , we also measured hyphal growth over time in WT and IRE1 ΔR macrophages and found that C. albicans hyphal growth is increased at 4 hpi in IRE1 ΔR macrophages (Fig. 7C).…”

“We've got to get out”—Strategies of human pathogenic fungi to escape from phagocytes

“…Growing hyphae generate physical forces that lead to rupture of the phagosome membrane, ultimately piercing of macrophage plasma membranes, and escape within a few hours (Dunker et al, 2021; Ghosh et al, 2009; McKenzie et al, 2010; Westman et al, 2018; Westman et al, 2020). Host cells can counteract the phagosomal membrane stress to a certain degree by folding internalized hyphae (Bain et al, 2021) or enlarging the phagosome via lysosomal fusion events (Domingues et al, 2022; Westman et al, 2020; Yang et al, 2020).…”