Gut mucosal type-2 immunity to parasitic infections

肠粘膜2型对寄生虫感染的免疫力

• 批准号: 10285591
• 负责人: Reinhard Hinterleitner
• 金额: $ 19.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285591
• 关键词: Acute; Anemia; Architecture; Back; Binding; Biological Assay; C-terminal; Candidate Disease Gene; Cell Death; Cell physiology; Cells; Cleaved cell; Containment; Data; Enteral; Epithelial; Epithelial Cells; Family member; Gene Cluster; Gene Expression; Gene Family; Genes; Genetic Transcription; Goals; Goblet Cells; Gut Mucosa; Health; Helminths; Homologous Gene; Human; Hyperplasia; Immune; Immune response; Immunity; In Vitro; Infection; Inflammation; Interleukin-13; Interleukins; Intestinal parasite; Intestines; Knockout Mice; Lead; Licensing; Lymphoid Cell; Mediating; Membrane; Membrane Lipids; Molecular; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Mus; N-terminal; Nematospiroides dubius; Nippostrongylus; Organoids; Parasites; Parasitic infection; Play; Process; Production; Proteins; Publishing; Regulation; Role; Signal Transduction; Small Intestines; Stimulus; System; Testing; Tissues; Trichomonadida; Tritrichomonas; Up-Regulation; chronic infection; cytokine; defense response; effective therapy; enteric infection; eosinophil; experimental study; gastrointestinal; gastrointestinal epithelium; gastrointestinal infection; global health; helminth infection; in vivo; inflammatory disease of the intestine; intestinal epithelium; malignant breast neoplasm; mast cell; microbial; mouse model; novel; recruit; response; tissue injury

Project Summary Enteric helminth and protist infections remain a significant global health problem. Although infections by these parasites are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anemia and malnourishment. Infections are strongly associated with protective type-2 immune mediated intestinal inflammation, observed across species, including mice and humans, and characterized by innate lymphoid cell (ILC2), eosinophil, and mast cell recruitment and tissue injury. Mouse models of infection with intestinal parasites have been established to study the cellular and molecular mechanisms of type-2 immune responses in greater detail: Helminths, such as Nippostrongylus brasiliensis and Heligmosomoides polygyrus, and certain protists of the order Trichomonadida induce acute host type-2 immune defense responses in the small intestine upon infection. Type-2 immune responses are initiated by parasite sensing interleukin-25 (IL-25) producing epithelial tuft cells, resulting in the activation of IL-13 producing ILC2 that in turn signal back on epithelial cells. This feedforward IL-25-ILC2-IL-13 circuit amplifies type-2 immune responses and initiates massive tissue remodeling including tuft- and goblet cell hyperplasia, and mucus production resulting in the containment of intestinal parasites. Despite the recent advancement in our understanding in immune-tissue crosstalk in type-2 mediated inflammation, we lack a complete understanding of the detailed processes underlying parasite-induced type-2 immune responses in the gut; these limits effective treatment options to enteric parasitic infections. To characterize type-2 mediated inflammation in the intestine in greater detail we screened for novel players implicated in intestinal type-2 inflammation. We identified a set of highly homologous genes that were significantly upregulated in the intestine upon type-2 inducing parasitic infections in vivo and in small intestinal organoid cultures upon IL-13 stimulating conditions in vitro. The goal of this proposal is therefore to study the role of these newly identified type-2 inducible genes in the protective type-2 immunity to protists and helminths and their function in intestinal epithelial cells. We generated knock-out mice and use a retroviral expression system in small intestinal organoid cultures. In aim 1, we will study the role of these candidate genes in host type-2 immune responses to protists and helminths in vivo and in aim 2 we will assess their function in intestinal epithelial cells under type-2 immune stimulating conditions in vitro. These findings may provide rational approaches to modulate type-2 inflammation to enteric parasite infections in humans.

项目总结