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

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

Author information

1
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Health, Sciences, and Technology, Massachusetts Institute of Technology, Boston, MA 02139, USA.
3
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
4
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: hung@molbio.mgh.harvard.edu.

Erratum in

  • Cell. 2015 Oct 8;163(2):523.

Abstract

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.

PMID:
26343579
PMCID:
PMC4578813
DOI:
10.1016/j.cell.2015.08.027
[Indexed for MEDLINE]
Free PMC Article

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