Fig. 2

SARS-CoV-2 infects epithelial cells of the nasopharyngeal tract and enters the cytoplasm. Here, the Spike protein and the M-protein inhibit cytoplasmic pathogen-recognition receptors (PRRs) like RIG-I and MDA-5. This results in abrogated stimulation of interferon (IFN) regulatory factors (IRFs), which are key to eliciting an antiviral type I and type III IFN response. Below the infected epithelium sentinel immune cells like macrophages (Mac) or plasmacytoid dendritic cells (pDCs) encounter the virus by endosomal uptake. In the endosome, binding of single stranded RNA of SARS-CoV-2 results in activation of TLR7. In the case of an active toll-like receptor (TLR)7-signaling pathway (left), TLR7-engagement results in a cytokine and interferon response. This secondary IFN release by sentinel cells can bring about the antiviral response by augmenting natural killer (NK) and CD8 cytotoxic T cell activities, thereby containing infection with SARS-CoV-2, and preventing systemic spread. In contrast, vulnerable patients with either loss-of-function alleles of TLR7 or a downregulated TLR-signaling pathway prior to infection (right) lack also this second IFN response. Age-related inflammation or inflammation related to visceral adipose tissue (VAT) leads to an enhanced expression of microRNA-146a (miR-146). In turn, miR-146 targets downstream signaling molecules of the TLR7-pathway including interleukin-1 receptor-associated kinase 1 (IRAK1) or TNF receptor associated factor 6 (TRAF6). Ultimately, the response of the TLR7-signaling pathway is subdued even though the receptor TLR7 itself is sensing viral RNA, and the IFN response by sentinel cells is missing. SARS-CoV-2 can then spread systemically, thereby establishing severe forms of COVID-19 disease