Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Host Microbe. 2021 Sep 8;29(9):1407-1420.e5. doi: 10.1016/j.chom.2021.07.002. Epub 2021 Aug 3.
The parasite Cryptosporidium invades and replicates in intestinal epithelial cells and is a leading cause of diarrheal disease and early childhood mortality. The molecular mechanisms that underlie infection and pathogenesis are largely unknown. Here, we delineate the events of host cell invasion and uncover a mechanism unique to Cryptosporidium. We developed a screen to identify parasite effectors, finding the injection of multiple parasite proteins into the host from the rhoptry organelle. These factors are targeted to diverse locations within the host cell and its interface with the parasite. One identified effector, rhoptry protein 1 (ROP1), accumulates in the terminal web of enterocytes through direct interaction with the host protein LIM domain only 7 (LMO7) an organizer of epithelial cell polarity and cell-cell adhesion. Genetic ablation of LMO7 or ROP1 in mice or parasites, respectively, impacts parasite burden in vivo in opposite ways. Taken together, these data provide molecular insight into how Cryptosporidium manipulates its intestinal host niche.
寄生虫隐孢子虫会侵袭并在肠道上皮细胞中复制，是导致腹泻病和幼儿死亡的主要原因。其感染和发病机制的分子机制在很大程度上尚不清楚。在这里，我们描述了宿主细胞入侵的事件，并揭示了隐孢子虫特有的一种机制。我们开发了一种筛选方法来鉴定寄生虫效应子，发现从棒状体细胞器中将多种寄生虫蛋白注射到宿主中。这些因子靶向宿主细胞内的不同位置及其与寄生虫的接口。鉴定出的一种效应子，棒状体蛋白 1（ROP1），通过与宿主蛋白 LIM 结构域仅 7（LMO7）的直接相互作用，在肠细胞的终末网中积累，LMO7 是上皮细胞极性和细胞间黏附的组织者。分别在小鼠或寄生虫中敲除 LMO7 或 ROP1，会以相反的方式影响体内寄生虫负担。总之，这些数据为隐孢子虫如何操纵其肠道宿主小生境提供了分子见解。
