Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses

Encounters between immune cells and invading bacteria ultimately determine the course of infection. These interactions are usually measured in populations of cells, masking cell-to-cell variation that may be important for infection outcome. To characterize the gene expression variation that underlies distinct infection outcomes and monitor infection phenotypes, we developed an experimental system that combines single-cell RNA-seq with fluorescent markers. Probing the responses of individual macrophages to invading Salmonella, we find that variation between individual infected host cells is determined by the heterogeneous activity of bacterial factors in individual infecting bacteria. We illustrate how variable PhoPQ activity in the population of invading bacteria drives variable host type I IFN responses by modifying LPS in a subset of bacteria. This work demonstrates a causative link between host and bacterial variability, with cell-to-cell variation between different bacteria being sufficient to drive radically different host immune responses. This co-variation has implications for host-pathogen dynamics in vivo.National Institutes of Health (U.S.) (grant HG002295)National Institutes of Health (U.S.) (grant DK043351)National Institutes of Health (U.S.) (grant NIH U19AI109725)National Institutes of Health (U.S.) (grant NIH F32 HD075541-02)National Human Genome Research Institute (U.S.) ((CEGS) Center of Cell Circuits (P50 HG006193))Klarman Cell Observator