Effects of Salmonella infection on bone marrow macrophage progenitors

项目摘要 伤寒沙门氏菌（S.伤寒）是一种细菌性肠道病原体，引起伤寒， 这是发展中国家的一个主要问题。摄入后，S.伤寒是从 肠外组织，包括骨髓（BM）。沙门氏菌感染对骨髓的影响 功能不太清楚。这一问题具有重要意义，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细胞因子而被重编程。 细胞因子和微生物分子，并产生具有改变的性质的巨噬细胞。我们在我们的 初步研究表明，该菌的相关病原为S.鼠伤寒杆菌也在骨髓中定殖， 慢性感染使用这个模型，我们已经作出了新的观察，巨噬细胞产生自 感染沙门氏菌的小鼠的BM在基因表达方面发生了广泛的变化， 响应能力。这些改变包括许多干扰素的基线表达显著升高， 参与抗病毒防御的IFN-γ调节基因，沿着体外炎症反应的减弱。 用脂多糖（LPS）刺激。来自沙门氏菌感染的骨髓源性巨噬细胞（BMDM） 小鼠在过继转移给受体后限制病原体生长的能力也受损， 随后用致病性S.鼠伤寒我们的研究结果表明，慢性沙门氏菌 感染诱导BM HSPC中的改变，所述改变被传递到后代巨噬细胞以表现为 表型改变这些研究将进一步阐明其作用机制和功能意义 （1）扩大我们的收养转移研究，分析转移的移民， 巨噬细胞，以及它们对肠上皮细胞和其他免疫细胞的影响，和（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.