Escalating Threat Levels of Bacterial Infection Can Be Discriminated by Distinct MAPK and NF-κB Signaling Dynamics in Single Host Cells

Keara Lane; Marta Andres-Terre; Takamasa Kudo; Denise M Monack; Markus W Covert

doi:10.1016/j.cels.2019.02.008

Escalating Threat Levels of Bacterial Infection Can Be Discriminated by Distinct MAPK and NF-κB Signaling Dynamics in Single Host Cells

Cell Syst. 2019 Mar 27;8(3):183-196.e4. doi: 10.1016/j.cels.2019.02.008. Epub 2019 Mar 20.

Authors

Keara Lane¹, Marta Andres-Terre², Takamasa Kudo³, Denise M Monack⁴, Markus W Covert⁵

Affiliations

¹ Department of Bioengineering, Stanford, CA, USA; Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA.
² Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford, CA, USA.
³ Department of Bioengineering, Stanford, CA, USA; Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA; Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
⁴ Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA; Department of Microbiology and Immunology, Stanford, CA, USA. Electronic address: dmonack@stanford.edu.
⁵ Department of Bioengineering, Stanford, CA, USA; Allen Discovery Center for Systems Modeling of Infection, Stanford, CA, USA. Electronic address: mcovert@stanford.edu.

PMID: 30904375
DOI: 10.1016/j.cels.2019.02.008

Abstract

During an infection, immune cells must identify the specific level of threat posed by a given bacterial input in order to generate an appropriate response. Given that they use a general non-self-recognition system, known as Toll-like receptors (TLRs), to detect bacteria, it remains unclear how they transmit information about a particular threat. To determine whether host cells can use signaling dynamics to transmit contextual information about a bacterial stimulus, we use live-cell imaging to make simultaneous quantitative measurements of host MAPK and NF-κB signaling, two key pathways downstream of TLRs, and bacterial infection and load. This combined, single-cell approach reveals that NF-κB and MAPK signaling dynamics are sufficient to discriminate between (1) pathogen-associated molecular patterns (PAMPs) versus bacteria, (2) extracellular versus intracellular bacteria, (3) pathogenic versus non-pathogenic bacteria, and (4) the presence or absence of features indicating an active intracellular bacterial infection, such as replication and effector secretion.

Keywords: MAPKs; NF-κB; Salmonella; TLR signaling; dynamics; host-pathogen interactions; live-cell microscopy.

Publication types

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

MeSH terms

Animals
Bacterial Infections / immunology
Bacterial Infections / metabolism*
Cell Line
Escherichia coli
Female
Humans
Male
Mice
Mitogen-Activated Protein Kinase Kinases / metabolism
NF-kappa B / metabolism
RAW 264.7 Cells
Salmonella typhimurium
Signal Transduction*
Toll-Like Receptors / metabolism*

Substances

NF-kappa B
Toll-Like Receptors
Mitogen-Activated Protein Kinase Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding