General microbial exposure establishes sustained myelopoiesis to provide enhanced innate resistance to infection 2709

Abstract Description Bacterial infection of the bloodstream is a significant cause of morbidity and mortality worldwide. Studies with microbially experienced laboratory mice, produced by cohousing (CoH) with pet store mice, have provided insight on T cell biology not readily apparent in specific pathogen-free (SPF) mice. However, less is known about the impact of general microbial exposure on myeloid cell development and biology. Our data show the generalized microbial exposure experienced by CoH mice causes rapid (by d3), but sustained (d60), fundamental changes in early myeloid progenitor cells. CoH mice have more total bone marrow cells per femur, and an increased percentage and number of granulocyte/monocyte progenitors (GMP) within the lineage-cKit + (LK) subset, compared to SPF mice. Analysis of lineage-Sca1+cKit + (LSK) progenitors also showed a skewing toward MPP-granulocyte/monocyte (MPP-G/M) and away from MPP-lymphocyte (MPP-Ly) cells in CoH bone marrow. As such, CoH mice have an increase in CD115+ monocytes in the bone marrow and enhanced egress of Ly6ChiCD115+ monocytes from the bone marrow into the blood. CoH CD115+ monocytes have a higher mitochondrial content and metabolic activity, and show increased steady-state and LPS-induced TNF production. These features correlate with CoH mice being more resistant to systemic E. coli infection, and depletion of CD115+ monocytes abrogates this resistance. Thus, CoH mice reveal fresh perspectives on the innate immune response during bacteremia. Funding Sources Supported by NIH grants AI154527, GM140881, GM134880, AI165553 Topic Categories Hematopoiesis and Immune System Development (HEM)