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

Cell. 2015 Sep 10;162(6):1309-21. doi: 10.1016/j.cell.2015.08.027. Epub 2015 Sep 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Host-Pathogen Interactions*
  • Interferon Type I / immunology
  • Lipopolysaccharides / metabolism
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Salmonella Infections / immunology
  • Salmonella Infections / microbiology
  • Salmonella typhimurium / physiology*
  • Specific Pathogen-Free Organisms


  • Interferon Type I
  • Lipopolysaccharides

Associated data

  • GEO/GSE65528
  • GEO/GSE65529
  • GEO/GSE65530
  • GEO/GSE65531