Cell-cycle-gated feedback control mediates desensitization to interferon stimulation

Abstract

Cells use molecular circuits to interpret and respond to extracellular cues, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the type I interferon (IFN)-responsive regulatory network operates in single human cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1/early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback loops, enabling duration-dependent desensitization to repetitive stimulations.

Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

“…Moreover, USP18 alone was not sufficient to drive desensitization, pointing to a concerted role of both negative feedback regulators (USP18 and SOCS1) in this process [71]. These desensitization results were also seen in HeLa cells, and captured via a simple ODE model that phenomenologically modeled a fast positive loop via IRF9 and a delayed negative loop via USP18 [37]. The model successfully predicted IRF9 induction for pulsatile versus sustained IFN-α inputs, with sustained treatments leading to reduced IRF9 induction.…”

“…Finally, different spatiotemporal diffusion gradients of both the release of viral progeny and IFN-Is comprise the third layer of stochasticity, thereby exposing individual cells to different gradients of viruses and IFN-Is, a process that is further enhanced by complex tissue structures [41]. stochastic processes, (e.g., gene expression noise) [35][36][37]. It is thought that intrinsic gene expression noise results from the stochastic nature of biochemical reactions, whereas extrinsic gene expression noise results from cell-cell fluctuations of components that are involved in generating the response [38].…”

“…A study in human hepatocyte-derived cellular carcinoma cells showed that their priming with a high IFN-I dose (1400 pM) resulted in desensitization of cells, and was mediated by the negative regulators SOCS1 and USP18, whereas priming with a low dose (2.8 pM) hypersensitized the pathway [71]. Similarly, IFN-I priming of HeLa cells for 24 h led to desensitization, whereas priming for only 2 h led to hypersensitization [37]. Therefore, in hypersensitized cells, the all-or-nothing cellular decision upon viral exposure might be much shorter and more potent than in desensitized cells, enabling second responders to rapidly and effectively elicit antiviral responses [71].…”

Revisiting Pleiotropic Effects of Type I Interferons: Rationale for Its Prophylactic and Therapeutic Use Against SARS-CoV-2

“…Although most mammalian nucleated cells are capable of producing type I IFNs (12), plasmacytoid dendritic cells (pDCs) are the professional IFN producer cells (16). IFNs do not only function as direct antiviral proteins, they also have several other biological properties such as inhibition of cellular proliferation, immunomodulation (4) and even desensitization after activation of immune response (13,17), making their role in viral infections broader than just their direct antiviral activity.…”

“…Being IFN expression an accurately controlled process, after IFN exposure the cells undergo an IFN-desensitized state which allows them to recover from IFN signaling and thus avoid an exacerbated immunological activation that may result in tissue damage and organ failure, as occurs during uncontrolled inflammatory responses to viral infection associated to cytokine storm and high mortality (13,17). Some IFN desensitization mechanisms are mediated by ISGs (11).…”