Mazon-Moya Maria J, Willis Alexandra R, Torraca Vincenzo, Boucontet Laurent, Shenoy Avinash R, Colucci-Guyon Emma, Mostowy Serge
Section of Microbiology, MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.
Institut Pasteur, Unité Macrophages et Développement de l'Immunité, Département de Biologie du Développement et des Cellules Souches, Paris, France.
PLoS Pathog. 2017 Jun 26;13(6):e1006467. doi: 10.1371/journal.ppat.1006467. eCollection 2017 Jun.
Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15-depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation.
福氏志贺菌是一种革兰氏阴性肠道侵袭性病原体，可导致人类肠道上皮发生炎症性破坏。福氏志贺菌感染已在体外得到充分研究，是细菌与宿主免疫系统相互作用的一个范例。最近的研究表明，细胞骨架成分在先天免疫和炎症控制中具有重要功能。Septins是高度保守的细胞骨架蛋白，已成为细菌感染先天免疫的关键参与者，但Septins在体内的功能尚不清楚。在这里，我们利用斑马鱼（Danio rerio）幼虫感染福氏志贺菌来研究Septins在体内炎症和感染控制中的作用。我们发现，人类SEPT7的斑马鱼直系同源物Sept15或Sept7b缺失会显著增加宿主对细菌感染的易感性。对缺失Sept15的幼虫进行活细胞成像显示，细菌负荷增加，中性粒细胞无法控制感染。令人惊讶的是，缺失Sept15的幼虫在感染福氏志贺菌后，Caspase-1活性显著增加，细胞死亡增多。用白细胞介素-1受体（IL-1R）拮抗剂阿那白滞素减弱炎症反应，可通过保护斑马鱼免受过度炎症和福氏志贺菌感染来抵消Sept15缺陷在体内的影响。这些发现突出了Septins在宿主抵御细菌感染中的新作用，并表明Septins功能障碍可能是过度炎症病例的一个潜在因素。
