Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells.
Interleukin-22 promotes phagolysosomal fusion to induce protection against Salmonella enterica Typhimurium in human epithelial cells.
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DOI：
10.1073/pnas.1811866115
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发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Dougan G
中科院分区：
文献类型：
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作者：
Forbester JL;Lees EA;Goulding D;Forrest S;Yeung A;Speak A;Clare S;Coomber EL;Mukhopadhyay S;Kraiczy J;Schreiber F;Lawley TD;Hancock REW;Uhlig HH;Zilbauer M;Powrie F;Dougan G
我们从患有婴儿炎症性肠病的患者的干细胞中产生了肠道类器官，该患者在IL 10 RB基因中具有纯合的功能丧失变体，使患者的细胞无法对白细胞介素-22做出反应。使用人类干细胞和小鼠模型，我们表明IL-22引发肠上皮细胞更有效地控制沙门氏菌感染，并且这种控制在患者类器官中减弱。通过将IL 10 RB基因的功能性拷贝引入患者的细胞中来恢复这种控制。这项工作证明了干细胞衍生的肠道类器官作为研究定义突变对病原体控制的影响的工具的实用性，表明类器官可以为发病机制研究提供宝贵的资源。肠上皮细胞（IEC）在调节免疫反应和控制感染中起着关键作用。然而，IEC在限制病原体方面的直接作用仍不完全清楚。在这里，我们提供的证据表明，IL-22引发的肠道类器官来源于健康的人诱导多能干细胞（hIPSC），以限制沙门氏菌肠道血清型鼠伤寒沙门氏菌SL 1344感染。转录组学、细菌侵袭试验和成像的结合表明，IL-22诱导的抗微生物活性是由IL-22预处理细胞中吞噬溶酶体融合增加驱动的。抗微生物表型在源自IL 10 RB基因中含有纯合突变的患者的hIPSC中不存在，该突变使IL-22受体失活，但通过遗传补充IL 10 RB缺陷而恢复。这项研究强调了IL-22途径促进人类肠上皮细胞控制微生物感染的机制。
We generated intestinal organoids from stem cells from a patient with infantile inflammatory bowel disease harboring a homozygous loss-of-function variant in the IL10RB gene, leaving the patient’s cells unable to respond to interleukin-22. Using both human stem cell and murine models, we show that IL-22 primes intestinal epithelial cells to control Salmonella infection more efficiently and that this control is abated in the patient organoids. This control is restored by introduction of a functional copy of the IL10RB gene into the patient’s cells. This work demonstrates the utility of stem cell-derived intestinal organoids as a tool for studying the effect of defined mutations on pathogen control, showing that organoids can provide an invaluable resource for pathogenesis research. Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22–induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22–pretreated cells. The antimicrobial phenotype was absent in hIPSCs derived from a patient harboring a homozygous mutation in the IL10RB gene that inactivates the IL-22 receptor but was restored by genetically complementing the IL10RB deficiency. This study highlights a mechanism through which the IL-22 pathway facilitates the human intestinal epithelium to control microbial infection.
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DOI：
10.1016/j.ymeth.2015.11.012
发表时间：
2016-03-01
期刊：
Methods (San Diego, Calif.)
影响因子：
--
作者：
Leha A;Moens N;Meleckyte R;Culley OJ;Gervasio MK;Kerz M;Reimer A;Cain SA;Streeter I;Folarin A;Stegle O;Kielty CM;HipSci Consortium;Durbin R;Watt FM;Danovi D
通讯作者：
Danovi D
影响因子：
5.7
作者：
Mottola G
通讯作者：
Mottola G
影响因子：
4.4
作者：
Dhiman, Rohan;Indramohan, Mohanalaxmi;Vankayalapati, Ramakrishna
通讯作者：
Vankayalapati, Ramakrishna
影响因子：
29.4
作者：
Grasberger H;El-Zaatari M;Dang DT;Merchant JL
通讯作者：
Merchant JL
影响因子：
30.3
作者：
Pham TA;Clare S;Goulding D;Arasteh JM;Stares MD;Browne HP;Keane JA;Page AJ;Kumasaka N;Kane L;Mottram L;Harcourt K;Hale C;Arends MJ;Gaffney DJ;Sanger Mouse Genetics Project;Dougan G;Lawley TD
通讯作者：
Lawley TD