Probes for INS

Coronavirus disease 2019 (COVID-19), caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by significant lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-193-5. While rapid induction of type I IFNs limits virus propagation, sustained elevation of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here, we identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a critical driver of aberrant type I IFN responses in COVID-1918. Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples of COVID-19 patients with prominent tissue destruction and associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a novel principle for the development of host-directed therapeutics.

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-β1 levels between smokers and non-smokers.