The surprising importance of gut microbiota in tackling flu infection

© Biotarget. All rights reserved. Biotarget 2020 | http://dx.doi. org/10.21037/biotarget.2020. 03.01 Our understanding of defence mechanisms raised against a given pathogen (e.g., influenza virus infection) is mainly focused on innate and adaptive immune cells responses, but other cell types such as stromal cells most certainly constitute an important first line of defence against invading pathogens. In addition to creating a primary physical barrier, stromal cells are armed with intrinsic immune defence mechanisms that cover a broad set of antiviral mechanisms including autophagy, inflammasome response, and the interferon (IFN) system. Cell autonomous immunity is tightly regulated, and needs to be unlocked by inflammatory signals including type-I interferon (IFN-I). Since the IFN-I receptor (composed of IFNAR1 and IFNAR2 subunits) is ubiquitously expressed, IFN-I acts as an alarm signal on both stromal and hematopoietic cells. Following binding to its cognate receptor, IFN-I elicits a potent antiviral state by inducing the expression of hundreds of genes collectively called IFN-stimulated genes (ISGs). Some ISGs carry intrinsic antiviral functions that were shown to dampen influenza virus replication including MX1, IFITM3, and NCOA7 among the most significant (1,2). Therefore, once established, the IFN-induced antiviral state endows the cells with the capacity to limit the replication and spread of several classes of viruses including influenza virus (3,4). Acute IFN-I production is triggered following sensing of invading pathogens by pattern recognition receptors (PRRs) that signal through MyD88, TRIF, MAVS or STING in order to activate the master regulators of IFN-I production, IRF3 and IRF7 transcription factors (5). However, this acute IFN production requires prior cell infection and is induced after a first wave of viral replication, therefore it cannot confer immediate antiviral defences. Moreover, viruses have evolved different strategies to avoid sensing and limit IFN induction. For instance, the NS1 protein from influenza virus acts through multiple anti-IFN strategies (6). Interestingly, in contrast to acute IFN production, pioneer observations reported a steady-state basal IFN production in absence of infection [reviewed in (7)]. This constitutive IFN production has gained much attention over the last decade and has revealed important roles in the regulation of immune cell function and homeostasis as well as for the maintenance of basal antiviral and antitumor immunity (7). Of note, dysregulated or chronic IFN production is associated with several pathological outcomes (8). Thus, IFN production requires a tight regulation in terms of timing and quantity. We can therefore ask, what are the molecular determinants that drive basal IFN production? How is it regulated by the host? By which mechanism does the steady-state IFN signature contribute to set basal antiviral defences? In a recent issue of Cell Reports, Bradley et al. (9) provided substantial answers to these burning questions (Figure 1). Bradley et al. (9) made the crucial observation that uninfected naïve mice present a significant level of ISG Editorial Commentary