Effects of Salmonella infection on bone marrow macrophage progenitors

项目总结 伤寒沙门氏菌(S.Typhi)是一种能引起伤寒的细菌性肠道病原体。 系统性疾病是发展中国家的一个主要问题。在摄入之后，伤寒沙门氏菌从 肠道到肠外组织，包括骨髓(BM)。沙门氏菌感染对骨髓的影响 功能还没有被很好地理解。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)通过暴露于感染相关的环境而重新编程 细胞因子和微生物分子，并产生具有改变性质的巨噬细胞。我们在我们的 相关病原体鼠伤寒沙门氏菌在小鼠骨髓中定植的初步研究 慢性感染。利用这个模型，我们做了一个新的观察，巨噬细胞是从 沙门氏菌感染小鼠的骨髓经历了广泛的基因表达和 响应性。这些改变包括大量干扰素的基线表达显著升高。 (干扰素)调节的参与抗病毒防御的基因，以及体外炎症反应减弱 内毒素(LPS)刺激。沙门氏菌感染的骨髓来源的巨噬细胞 将病原体过继转移给受体后，小鼠限制病原体生长的能力也会受到损害 随后用强毒力鼠伤寒沙门氏菌进行攻击。我们的结果表明慢性沙门氏菌 感染诱导骨髓HSPC的改变，这些改变被传递给后代巨噬细胞，表现为 改变了表型。拟议的研究将进一步表征这一机制和功能意义 通过(1)扩展我们的收养迁移研究来分析被转移者的迁移 巨噬细胞及其对肠上皮细胞和其他免疫细胞的影响；(2)比较 来自对照和沙门氏菌感染小鼠的BMDM的抗病毒能力。

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.