Grilo Ruivo Margarida T, Shin Ji-Hun, Lenz Todd, Matsuno Stephanie Y, Yanes Katherine Olivia, Graindorge Arnault, Hamie Maguy, Berry-Sterkers Laurence, Gissot Mathieu, El Hajj Hiba, Le Roch Karine G, Lodoen Melissa B, Lebrun Maryse, Penarete-Vargas Diana Marcela
Laboratory of Pathogens and Host Immunity, UMR 5294 CNRS, UA15 INSERM, Université de Montpellier, Montpellier, 34095, France.
Department of Molecular Biology and Biochemistry and the Institute for Immunology, University of California, Irvine, CA, 92697, USA.
Nat Commun. 2025 Jan 15;16(1):709. doi: 10.1038/s41467-025-56128-x.
Programmed-cell death is an antimicrobial defense mechanism that promotes clearance of intracellular pathogens. Toxoplasma counteracts host immune defenses by secreting effector proteins into host cells; however, how the parasite evades lytic cell death and the effectors involved remain poorly characterized. We identified ROP55, a rhoptry protein that promotes parasite survival by preventing lytic cell death in absence of IFN-γ stimulation. RNA-Seq analysis revealed that ROP55 acts as a repressor of host pro-inflammatory responses. In THP-1 monocytes ΔROP55 infection increased NF-κB p65 nuclear translocation, IL-1β production, and GSDMD cleavage compared to wild type or complemented parasites. ΔROP55 infection also induced RIPK3-dependent necroptosis in human and mouse primary macrophages. Moreover, ΔROP55 parasites were significantly impaired in virulence in female mice and prevented NF-κB activation and parasite clearance in mBMDM. These findings place ROP55 as a major virulence factor, dampening lytic cell death and enabling Toxoplasma to evade clearance from infected cells.
程序性细胞死亡是一种促进细胞内病原体清除的抗菌防御机制。弓形虫通过向宿主细胞分泌效应蛋白来对抗宿主免疫防御；然而，该寄生虫如何逃避裂解性细胞死亡以及涉及的效应蛋白仍知之甚少。我们鉴定出了ROP55，一种棒状体蛋白，它在没有IFN-γ刺激的情况下通过防止裂解性细胞死亡来促进寄生虫存活。RNA测序分析表明，ROP55作为宿主促炎反应的抑制因子发挥作用。与野生型或互补寄生虫相比，在THP-1单核细胞中，ΔROP55感染增加了NF-κB p65核转位、IL-1β产生和GSDMD裂解。ΔROP55感染还在人和小鼠原代巨噬细胞中诱导了RIPK3依赖性坏死性凋亡。此外，ΔROP55寄生虫在雌性小鼠中的毒力显著受损，并阻止了mBMDM中的NF-κB激活和寄生虫清除。这些发现表明ROP55是一种主要的毒力因子，可抑制裂解性细胞死亡并使弓形虫逃避被感染细胞的清除。
