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bioRxiv · 10.1101/2022.09.11.507479

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

Van Eyndhoven, L. C.·Verberne, V. P. G.·Bouten, C. V. C.·Singh, A.·Tel, J.
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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 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-Delbruck 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.

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Van Eyndhoven, L. C., Verberne, V. P. G., Bouten, C. V. C., Singh, A., Tel, J.. 2022-09-13. Transiently heritable fates and quorum sensing drive early IFN-I response dynamics. https://doi.org/10.1101/2022.09.11.507479

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