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.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Roi
R
Avraham
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Health, Sciences, and Technology, Massachusetts Institute of Technology, Boston, MA 02139, USA.
Nathan
N
Haseley
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Douglas
D
Brown
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Cristina
C
Penaranda
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.
Humberto B
HB
Jijon
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
John J
JJ
Trombetta
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Rahul
R
Satija
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alex K
AK
Shalek
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.
Ramnik J
RJ
Xavier
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.
Aviv
A
Regev
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.
Deborah T
DT
Hung
D000818:Animals; D054884:Host-Pathogen Interactions; D007370:Interferon Type I / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms
D007370:Interferon Type I; D008070:Lipopolysaccharides