PT  - JOURNAL ARTICLE
AU  - Van Eyndhoven, Laura C.
AU  - Verberne, Vincent P.G.
AU  - Bouten, Carlijn V.C.
AU  - Singh, Abhyudai
AU  - Tel, Jurjen
TI  - Transiently heritable fates and quorum sensing drive early IFN-I response dynamics
AID  - 10.1101/2022.09.11.507479
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.11.507479
4099  - http://biorxiv.org/content/early/2022/09/13/2022.09.11.507479.short
4100  - http://biorxiv.org/content/early/2022/09/13/2022.09.11.507479.full
AB  - 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 only limited to a fraction of 1-3% of the total population, both found in vitro and in vivo, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various host-intrinsic factors, both stochastic and epigenetic, on dictating early IFN-I responses. Hypomethylating drugs increased the percentage of responding cells. Next, with the classical Luria-Delbrück fluctuation test, we provided evidence that the fate of becoming a responding cell is transiently heritable. Finally, while studying varying cell-densities, we substantiated an important role for quorum sensing, which was verified by mathematical modeling. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding of cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems, and ultimately will improve IFN-I based immune therapies.Competing Interest StatementThe authors have declared no competing interest.