Combinatorial processing of bacterial and host-derived innate immune stimuli at the single-cell level

Miriam V. Gutschow, John C. Mason, Keara Michelle Lane, Inbal Maayan, Jacob J. Hughey, Bryce T. Bajar, Debha N. Amatya, Sean D. Valle, Markus W. Covert*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

During the course of a bacterial infection, cells are exposed simultaneously to a range of bacterial and host factors, which converge on the central transcription factor nuclear factor (NF)-κB. How do single cells integrate and process these converging stimuli? Here we tackle the question of how cells process combinatorial signals by making quantitative single-cell measurements of the NF-κB response to combinations of bacterial lipopolysaccharide and the stress cytokine tumor necrosis factor. We found that cells encode the presence of both stimuli via the dynamics of NF-κB nuclear translocation in individual cells, suggesting the integration of NF-κB activity for these stimuli occurs at the molecular and pathway level. However, the gene expression and cytokine secretion response to combinatorial stimuli were more complex, suggesting that other factors in addition to NF-κB contribute to signal integration at downstream layers of the response. Taken together, our results support the theory that during innate immune threat assessment, a pathogen recognized as both foreign and harmful will recruit an enhanced immune response. Our work highlights the remarkable capacity of individual cells to process multiple input signals and suggests that a deeper understanding of signal integration mechanisms will facilitate efforts to control dysregulated immune responses.

Original languageEnglish (US)
Pages (from-to)282-292
Number of pages11
JournalMolecular biology of the cell
Volume30
Issue number2
DOIs
StatePublished - Jan 15 2019

Funding

We thank K. C. Huang, David Schneider, Denise Monack, Justin Sonnenburg, and members of the Covert lab for helpful discussions and comments on the manuscript. Some of the computing for this project was performed on the Sherlock cluster. We thank Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. We also gratefully acknowledge an Allen Discovery Center Award, a National Institutes of Health (NIH) R21 (5R21AI104305-02), the Stanford Center for Systems Biology (NIH P50GM107615), an NIH Pioneer Award (5DP1LM01150-05), and an Allen Distinguished Investigator Award to M.W.C., Siebel, Weiland Family, and Rensselaer Engineering Fellowships to M.V.G., a National Institute of Standards and Technology (NIST) Training Grant and Agilent Bioengineering Fellowship to J.C.M., and Bio-X and Achievement Rewards for College Scientists (ARCS) Fellowships to J.J.H.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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