Effects of Salmonella infection on bone marrow macrophage progenitors

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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.