Browsing by Author "Preising, Nico"

Abstract SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

Significance G protein-coupled receptors (GPCRs) are involved in many physiological processes and important drug targets. However, most therapeutic agents targeting GPCRs, such as the coreceptors of HIV-1 CCR5 and CXCR4, also interfere with their signaling function. Here, we used primate lentiviruses as tools to discover novel endogenous ligands of GPR15, a coreceptor for HIV-2 and SIV proposed to play a role in mucosal immunity. We found that C-terminal fragments of cystatin C generated by immune-activated proteases inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L chemokine signaling. Thus, we identified an endogenous bioactive peptide that specifically prevents the detrimental activity of a GPCR (i.e. virus infection) without compromising its physiological signaling function.