美国国家过敏和传染病研究所Michail S. Lionakis团队发现，系统性真菌感染期间C5a许可的吞噬细胞驱动杀菌免疫。2023年5月22日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员发现补体系统基因的转录是在念珠菌病患者中诱发的最主要的生物途径，并且可以预测念珠菌病。在机制上，C5a-C5aR1通过刺激吞噬细胞的效应功能和感染组织中ERK和AKT依赖性的存活，在系统性念珠菌病的小鼠模型中促进真菌清除和宿主存活。C5ar1的去除重新引导巨噬细胞在mTOR下游的代谢，促进其凋亡并通过肾脏损伤提高死亡率。除了肝细胞产生的C5，吞噬细胞本身产生的局部C5也为抗真菌保护提供了一个关键的底物。较低的血清C5a浓度或降低白细胞C5表达的C5多态性与患者的不良结局独立相关。因此，在系统性真菌感染期间，局部的、来自于吞噬细胞的C5产生许可了吞噬细胞的抗菌功能并赋予了先天保护。
据了解，全身念珠菌病是一种常见的、高死亡率的、医院内真菌感染。出乎意料的是，它已成为抗补体C5靶向单克隆抗体治疗的并发症，表明C5在抗真菌免疫中具有关键地位。
附：英文原文
Title: C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection
Author: Jigar V. Desai, Dhaneshwar Kumar, Tilo Freiwald, Daniel Chauss, Melissa D. Johnson, Michael S. Abers, Julie M. Steinbrink, John R. Perfect, Barbara Alexander, Vasiliki Matzaraki, Brendan D. Snarr, Marissa A. Zarakas, Vasileios Oikonomou, Lakmali M. Silva, Raju Shivarathri, Emily Beltran, Luciana Negro Demontel, Luopin Wang, Jean K. Lim, Dylan Launder, Heather R. Conti, Muthulekha Swamydas, Micah T. McClain, Niki M. Moutsopoulos, Majid Kazemian, Mihai G. Netea, Vinod Kumar, Jrg Khl, Claudia Kemper, Behdad Afzali, Michail S. Lionakis
Issue&Volume: 2023-05-22
Abstract: Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly,it has emerged as a complication of anti-complement C5-targeted monoclonal antibodytreatment, indicating a critical niche for C5 in antifungal immunity. We identifiedtranscription of complement system genes as the top biological pathway induced incandidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promotedfungal clearance and host survival in a mouse model of systemic candidiasis by stimulatingphagocyte effector function and ERK- and AKT-dependent survival in infected tissues.C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosisand enhancing mortality through kidney injury. Besides hepatocyte-derived C5, localC5 produced intrinsically by phagocytes provided a key substrate for antifungal protection.Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derivedC5 production licenses phagocyte antimicrobial function and confers innate protectionduring systemic fungal infection.
DOI: 10.1016/j.cell.2023.04.031
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00465-8