General microbial exposure tightens infection bottlenecks to reduce the likelihood of infection and systemic dissemination 2708

Abstract Description Microbial pathogens face a variety of barriers – or bottlenecks – during infection. The importance of bottlenecks is well-recognized, based on their ability to influence host susceptibility to pathogen colonization, paths of dissemination within individual hosts, and transmission potential between hosts. However, the impact of host mechanisms, especially those mediated by the immune system, that influence bottleneck size remains to be fully delineated. Microbially-experienced mice, generated by cohousing (CoH) with pet store mice, display resistance to Gram-negative bacteremia vs. specific pathogen-free (SPF) mice, as evidenced by reduced bacterial burden across multiple tissues within the first 24 hr after infection and increased survival. To determine how general microbial exposure impacts infection bottlenecks, we used barcoded E. coli to perform bacterial lineage tracing in vivo and quantification of infection bottlenecks. CoH mice had tighter infection bottlenecks than SPF mice, which correlated with decreased pathogen burden at 24- and 72-hr post-infection. Flow cytometric analysis of the lung and spleen found increased frequency and numbers of CD11b+Ly6G- monocytes after infection in CoH mice but decreased in SPF mice. Monocyte depletion from CoH mice prior to infection revealed these cells were essential for tightening infection bottlenecks and controlling pathogen burden. Funding Sources Supported by NIH grant GM140881, HHMI Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)