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

• Published in: eLife Vol. 12
• Main Authors: Van Eyndhoven, Laura C, Verberne, Vincent P G, Bouten, Carlijn V C, Singh, Abhyudai, Tel, Jurjen
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 11-01-2023; eLife Sciences Publications, Ltd
• Subjects: Animals; Antiviral Agents; Antiviral drugs; Cell Biology; Cell cycle; Cell density; cellular decision-making; Communication; Cytokines; Decision making; Determinism; Drug resistance; Epigenetics; Fibroblasts; Gene expression; Heritability; Immunology and Inflammation; Immunosuppressive agents; Interferon; Interferon Type I - metabolism; interferons; Mathematical models; Mice; Ordinary differential equations; Pathogenesis; Phosphorylation; Population density; Quorum sensing; Quorum Sensing - genetics; Signal Transduction; Stochastic models; Stochasticity; Viral infections; Virus Diseases; cellular decision-making; mouse; cell biology; interferons; quorum sensing; inflammation; stochasticity; immunology; epigenetics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83055

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.