Toll-like receptors (TLRs) play a pivotal role in the initiation of anti-infectious immune responses. Distinct pathogen-associated molecular patterns (PAMPs) are recognized by different TLRs, at the cell surface or in endosomes. TLR7 and TLR8 are endosomal receptors that share structural homology and sense viral single stranded (ss) RNA. The endosomal distribution of TLR7 and TLR8 allows them to scan for the presence of viral RNA in the phagocytic cargo. Their activation leads to NF-κB-, AP1- and IRF-mediated production of type-I IFNs (IFN-α/β) and pro-inflammatory cytokines. After cellular detection of the viral entry into a host cell, interferon (IFN) induction of interferon stimulated genes (ISGs) is essential for host antiviral defense. Recently it was found that ISGs are upregulated in ACE2 expressing cells, and in particular that IFN-alpha drives ACE2 expression. As SARS-CoV-S leads to ACE2-receptor-mediated internalization, the host IFN response could thus promote the ability for SARS-CoV and SARS-CoV-2 to maintain cellular targets in neighboring human upper airway epithelial cells.