Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2024 Sep 16;15(1):8129. doi: 10.1038/s41467-024-52233-5.
When an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced. C. elegans employ multiple defense systems to ensure survival when exposed to Pseudomonas aeruginosa including activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtype C. elegans quickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defenses capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals interesting insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.
当生物体遇到病原体时，宿主先天免疫系统会被激活，以抵御病原体的定植和产生的有毒异源物质。秀丽隐杆线虫采用多种防御系统来确保在暴露于铜绿假单胞菌时的生存，包括激活细胞保护转录因子 SKN-1/NRF2。尽管野生型秀丽隐杆线虫在接触 PA14 时会迅速学会避免病原体，但我们在这里描述了一种特殊的冷漠样行为，即在 SKN-1 持续激活的动物中，即使存在非致病性和促进健康寿命的食物选择，动物也选择不离开并继续食用病原体。尽管缺乏逃离感染环境的紧迫性，但持续激活 SKN-1 的动物并非对病原体的存在一无所知，它们会表现出典型的病原体诱导的肠道扩张和最终死亡。SKN-1 的激活，特别是在神经元和肠道组织中，协调了一个独特的转录程序，导致需要神经元和非神经元组织都参与的 5-羟色胺信号传导缺陷。SKN-1 激活导致 5-羟色胺耗竭，限制了病原体防御能力，驱动与病原体相关的冷漠行为，并诱导对选择性 5-羟色胺再摄取抑制剂的合成敏感性。总之，我们的工作揭示了有趣的见解，即动物如何感知环境病原体，随后改变行为和细胞程序以促进生存。
