Yang Mabel, Walpole Glenn F W, Westman Johannes
Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Microb Cell. 2020 Dec 3;7(12):323-325. doi: 10.15698/mic2020.12.738.
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, is a commensal polymorphic fungus that colonizes ~50% of the population and can cause life-threatening infections in immunocompromised patients. Not only can 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 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.
专业吞噬细胞通过其摄取、吞噬和消化细胞外环境物质的特殊能力，成为固有免疫和组织稳态的关键节点。吞噬细胞的降解和杀菌功能依赖于溶酶体与吞噬体等内体区室的融合，从而实现对内化猎物和碎片的消化与再循环。尽管如此，仍有几种特别危险的感染是由一类顽强的病原体引起的，这些病原体能够抵抗消化，常常在吞噬体膜内生存甚至增殖。一个这样的例子是一种共生多态真菌，它定植于约50%的人群中，可在免疫功能低下的患者中引起危及生命的感染。它不仅能在吞噬体内存活，而且巨噬细胞对它的摄取会引发酵母到菌丝的转变，促进吞噬体内的快速生长（每小时几微米），同时给围绕真菌的吞噬体膜带来巨大的机械负担。维持膜的完整性对于保持吞噬体的恶劣内部环境、降解酶的功能和氧化应激至关重要。然而，诸如吞噬体之类的生物膜伸展能力有限。以该真菌作为细胞内病原体模型，我们最近的研究揭示了一种机制，通过该机制吞噬体通过扩大其表面积来应对病原体在吞噬体内的生长，从而维持吞噬体膜的完整性。我们推测这种扩张将通过来自外部来源的膜与吞噬体的递送和融合来促进。一致的是，巨噬细胞通过拉伸诱导的吞噬体钙释放来响应酵母到菌丝的转变，从而导致溶酶体的募集和插入，以适应吞噬溶酶体的扩张并保持其完整性。下面，我们将讨论这种溶酶体插入的钙依赖性机制，作为避免吞噬体破裂的一种手段。此外，我们通过关注真菌应激反应、营养获取、炎性小体激活和细胞死亡，来研究膜完整性对宿主与病原体之间微妙平衡的影响。
