Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
PLoS Pathog. 2023 May 4;19(5):e1011372. doi: 10.1371/journal.ppat.1011372. eCollection 2023 May.
Giardia intestinalis is a non-invasive, protozoan parasite infecting the upper small intestine of most mammals. Symptomatic infections cause the diarrhoeal disease giardiasis in humans and animals, but at least half of the infections are asymptomatic. However, the molecular underpinnings of these different outcomes of the infection are still poorly defined. Here, we studied the early transcriptional response to G. intestinalis trophozoites, the disease-causing life-cycle stage, in human enteroid-derived, 2-dimensional intestinal epithelial cell (IEC) monolayers. Trophozoites preconditioned in media that maximise parasite fitness triggered only neglectable inflammatory transcription in the IECs during the first hours of co-incubation. By sharp contrast, "non-fit" or lysed trophozoites induced a vigorous IEC transcriptional response, including high up-regulation of many inflammatory cytokines and chemokines. Furthermore, "fit" trophozoites could even suppress the stimulatory effect of lysed trophozoites in mixed infections, suggesting active G. intestinalis suppression of the IEC response. By dual-species RNA-sequencing, we defined the IEC and G. intestinalis gene expression programs associated with these differential outcomes of the infection. Taken together, our results inform on how G. intestinalis infection can lead to such highly variable effects on the host, and pinpoints trophozoite fitness as a key determinant of the IEC response to this common parasite.
肠道贾第虫是一种非侵袭性的原生动物寄生虫，感染大多数哺乳动物的小肠上部。有症状的感染会导致人类和动物的腹泻病贾第虫病，但至少有一半的感染是无症状的。然而，感染这些不同结果的分子基础仍未得到很好的定义。在这里，我们研究了人类肠类器官衍生的二维肠上皮细胞（IEC）单层中，致病生命周期阶段的肠道贾第虫滋养体的早期转录反应。在与 IEC 共孵育的最初几个小时内，在最大程度上适应寄生虫适应性的培养基中预培养的滋养体仅触发 IEC 中可忽略不计的炎症转录。相比之下，“非适应”或裂解的滋养体诱导了强烈的 IEC 转录反应，包括许多炎症细胞因子和趋化因子的高上调。此外，“适应”的滋养体甚至可以抑制混合感染中裂解的滋养体的刺激作用，这表明肠道贾第虫积极抑制 IEC 对感染的反应。通过双物种 RNA-seq，我们定义了与感染这些不同结果相关的 IEC 和肠道贾第虫的基因表达程序。总之，我们的研究结果说明了肠道贾第虫感染如何对宿主产生如此多样化的影响，并确定了滋养体适应性是 IEC 对这种常见寄生虫反应的关键决定因素。
