Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

Laura Christine Van Eyndhoven; Vincent P.G. Verberne; Carlijn V.C. Bouten; Abhyudai Singh; Jurjen Tel

doi:10.7554/eLife.83055

Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

Laura Christine Van Eyndhoven, Vincent P.G. Verberne, Carlijn V.C. Bouten, Abhyudai Singh, Jurjen Tel (Corresponding author)

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Abstract

Type I Interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is limited to only fractions of 1-3% of the total population, both found in vitro, in vivo, and across cell types, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various stochastic and deterministic host-intrinsic factors on dictating early IFN-I responses, using a murine fibroblast reporter model. Epigenetic drugs influenced the percentage of responding cells. Next, with the classical Luria-Delbrück fluctuation test, we provided evidence for transient heritability driving responder fates, which was verified with mathematical modeling. Finally, while studying varying cell-densities, we substantiated an important role for cell density in dictating responsiveness, similar to the phenomenon of quorum sensing. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding on cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems.

Original language	English
Article number	e83055
Number of pages	25
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.83055
Publication status	Published - 11 Jan 2023

Funding

The authors would like to thank Ulfert Rand, Hansjörg Hauser, and Mario Köster for providing the reporter cells. Additionally, the authors would like to thank Nidhi Sinha and Bart M Tiemeijer for the enthusiastic, insightful, and lively discussions. This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 802791). Finally, the authors would like to acknowledge the generous support by the Eindhoven University of Technology.

Funders	Funder number
European Union's Horizon 2020 - Research and Innovation Framework Programme	802791
H2020 European Research Council
Eindhoven University of Technology

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title = "Transiently heritable fates and quorum sensing drive early IFN-I response dynamics",

abstract = "Type I Interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is limited to only fractions of 1-3% of the total population, both found in vitro, in vivo, and across cell types, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various stochastic and deterministic host-intrinsic factors on dictating early IFN-I responses, using a murine fibroblast reporter model. Epigenetic drugs influenced the percentage of responding cells. Next, with the classical Luria-Delbr{\"u}ck fluctuation test, we provided evidence for transient heritability driving responder fates, which was verified with mathematical modeling. Finally, while studying varying cell-densities, we substantiated an important role for cell density in dictating responsiveness, similar to the phenomenon of quorum sensing. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding on cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems. ",

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Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

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