Department of Biological Sciences, Clemson University, Clemson, South Carolina, United States of America.
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS Pathog. 2022 Mar 25;18(3):e1010040. doi: 10.1371/journal.ppat.1010040. eCollection 2022 Mar.
Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Increased germination and invasive hyphal growth is also observed in infected F0 crispant larvae with mutations in genes encoding for COX enzymes (ptgs2a/b). Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae.
侵袭性曲霉病是一种常见的机会性感染，导致免疫功能低下的感染者 >50%的死亡率。固有免疫系统防止免疫功能正常个体发生侵袭性曲霉病的具体分子机制尚不完全清楚。在这里，我们使用斑马鱼幼虫-烟曲霉感染模型来确定环氧化酶 (COX) 酶信号作为促进宿主存活的一种机制。与对照幼虫相比，暴露于泛 COX 抑制剂吲哚美辛的幼虫因感染而死亡的比例明显更高。COX 信号转导既受巨噬细胞介导，也受中性粒细胞介导。然而，吲哚美辛处理对吞噬细胞的募集没有影响。相反，COX 信号转导促进吞噬细胞介导的抑制发芽和侵袭性菌丝生长。在编码 COX 酶的基因（ptgs2a/b）发生突变的感染 F0 脆化幼虫中，也观察到发芽和侵袭性菌丝生长增加。增加的发芽和侵袭性菌丝生长也发生在感染了烟曲霉的斑马鱼幼虫中。保护性 COX 介导的信号转导需要受体 EP2 和外源性前列腺素 E2 (PGE2)，以挽救吲哚美辛诱导的对真菌生长的免疫控制降低。总的来说，我们发现 COX 信号转导通过斑马鱼幼虫中的吞噬细胞激活 PGE2-EP2 途径，增加对烟曲霉菌丝生长的控制。
