Innate immune sensing serves as the first line of antiviral defense and is essential for immunity to viruses. To date, our understanding of the specific innate immune response to SARS-CoV-2 is extremely limited. However, the virus-host interactions involving SARS-CoV-2 are likely to recapitulate many of those involving other CoVs, given the shared sequence homology among CoVs and the conserved mechanisms of innate immune signaling. In the case of RNA viruses such as SARS-CoV-2, these pathways are initiated through the engagement of pattern-recognition receptors (PRRs) by viral single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) via cytosolic RIG-I like receptors (RLRs) and extracellular and endosomal Toll-like receptors (TLRs). Upon PRR activation, downstream signaling cascades trigger the secretion of cytokines. Among these, type I/III interferons (IFNs) are considered the most important for antiviral defense, but other cytokines, such as proinflammatory tumor necrosis factor alpha (TNF-α), and interleukin-1 (IL-1), IL-6, and IL-18 are also released. Together, they induce antiviral programs in target cells and potentiate the adaptive immune response. If present early and properly localized, IFN-I can effectively limit CoV infection (Channappanavar et al., 2016, Channappanavar et al., 2019). Early evidence demonstrated that SARS-CoV-2 is sensitive to IFN-I/III pretreatment in vitro, perhaps to a greater degree than SARS-CoV-1 (Blanco-Melo et al., 2020, Lokugamage et al., 2020, Mantlo et al., 2020, Stanifer et al., 2020). However, the specific IFN-stimulated genes (ISGs) that mediate these protective effects are still being elucidated. Lymphocyte antigen 6 complex locus E (LY6E) has been shown to interfere with SARS-CoV-2 spike (S) protein-mediated membrane fusion (Pfaender et al., 2020, Zhao et al., 2020c). Likely, the IFN-induced transmembrane family (IFITM) proteins inhibit SARS-CoV-2 entry, as demonstrated for SARS-CoV-1 (Huang et al., 2011b), although their action in promoting infection has also been described for other CoVs (Zhao et al., 2014, Zhao et al., 2018).