Effects of Salmonella infection on bone marrow macrophage progenitors

沙门氏菌感染对骨髓巨噬细胞祖细胞的影响

• 批准号: 10405563
• 负责人: Bobby Joseph Cherayil
• 金额: $ 25.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405563
• 关键词: 2019-nCoV; Adoptive Transfer; Animals; Attenuated; Biological Assay; Blood specimen; Bone Marrow; Cells; Characteristics; Chronic; Defect; Development; Epigenetic Process; Epithelial Cells; Exposure to; Food Contamination; Gene Expression; Genes; Gentamicins; Growth; Hematopoietic stem cells; Human; Immune; Immunity; Impairment; In Vitro; Individual; Infection; Inflammation Mediators; Inflammatory; Inflammatory Response; Influenza A virus; Ingestion; Interferon Type II; Interferon-alpha; Interferons; Intestines; Knowledge; Lipopolysaccharides; Long-Term Effects; Memory; Metabolic; Modeling; Mus; Oral; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Predisposition; Property; Pulmonary Pathology; Resistance; Salmonella; Salmonella infections; Salmonella typhi; Salmonella typhimurium; Suggestion; Testing; Time; Tissues; Toll-like receptors; Training; Transcript; Typhoid Fever; Up-Regulation; Variant; Viral; Viral Genes; Viral Load result; Viral Physiology; Virulent; Virus; Virus Diseases; base; chronic infection; contaminated water; cytokine; enteric pathogen; experimental study; immune function; in vivo; influenza virus strain; insight; interest; intestinal epithelium; macrophage; microbial; migration; mouse model; novel; pandemic disease; pathogen; pathogenic virus; progenitor; response; transcriptional reprogramming; transcriptome sequencing

PROJECT SUMMARY Salmonella enterica serovar Typhi (S. Typhi) is a bacterial enteropathogen that causes typhoid fever, a systemic illness that is a major problem in the developing world. Following ingestion, S. Typhi spreads from the gut to extra-intestinal tissues, including the bone marrow (BM). The effects of Salmonella infection on BM function are not well understood. This issue is of significance since recent studies indicate that BM hematopoietic stem and progenitor cells (HSPCs) are reprogrammed by exposure to infection-associated cytokines and microbial molecules and give rise to macrophages with altered properties. We have found in our preliminary studies that the related pathogen S. Typhimurium also colonizes the BM in a mouse model of chronic infection. Using this model, we have made the novel observation that macrophages generated from the BM of the Salmonella-infected mice have undergone extensive changes in gene expression and responsiveness. These alterations include significantly elevated baseline expression of numerous interferon (IFN)-regulated genes involved in anti-viral defense, along with diminished inflammatory responses to in vitro stimulation with lipopolysaccharide (LPS). BM-derived macrophages (BMDMs) from the Salmonella-infected mice are also impaired in their ability to restrict pathogen growth following adoptive transfer to recipients that are subsequently challenged with virulent S. Typhimurium. Our results suggest that chronic Salmonella infection induces alterations in BM HSPCs that are transmitted to progeny macrophages to manifest as an altered phenotype. The proposed studies will further characterize the mechanisms and functional significance of these findings by (1) extending our adoptive transfer studies to analyze migration of the transferred macrophages, as well as their effects on intestinal epithelial cells and other immune cells, and (2) comparing the anti-viral capabilities of BMDMs from control and Salmonella-infected mice.

项目概要 伤寒沙门氏菌 (S. Typhi) 是一种细菌性肠道病原体，可引起伤寒， 系统性疾病是发展中国家的一个主要问题。摄入后，伤寒沙门氏菌从 肠道到肠外组织，包括骨髓（BM）。沙门氏菌感染对 BM 的影响 功能不太了解。这个问题很重要，因为最近的研究表明 BM 造血干细胞和祖细胞 (HSPC) 通过暴露于与感染相关的环境而被重新编程 细胞因子和微生物分子，并产生具有改变特性的巨噬细胞。我们发现在我们的 初步研究表明，相关病原体鼠伤寒沙门氏菌也在小鼠模型的 BM 中定植 慢性感染。使用这个模型，我们进行了新的观察，即巨噬细胞从 感染沙门氏菌的小鼠的骨髓中基因表达发生了广泛的变化， 反应能力。这些改变包括多种干扰素的基线表达显着升高 (IFN) 调节的基因参与抗病毒防御，并减少体外炎症反应 脂多糖（LPS）刺激。来自沙门氏菌感染者的 BM 衍生巨噬细胞 (BMDM) 小鼠在过继转移给受体后限制病原体生长的能力也受到损害 随后受到剧毒鼠伤寒沙门氏菌的攻击。我们的结果表明慢性沙门氏菌 感染引起 BM HSPC 的改变，这些改变被传递给子代巨噬细胞，表现为 改变的表型。拟议的研究将进一步表征其机制和功能意义 通过 (1) 扩展我们的收养转移研究来分析被转移者的迁移 巨噬细胞，以及它们对肠上皮细胞和其他免疫细胞的影响，以及（2）比较 对照小鼠和沙门氏菌感染小鼠的 BMDM 的抗病毒能力。