Xiujuan Zhang

The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) initiates the infection process by binding to the viral cellular receptor angiotensin-converting enzyme 2 through the receptor-binding domain (RBD) in the S1 subunit of the viral spike (S) protein. This event is followed by virus-cell membrane fusion mediated by the S2 subunit, which allows virus entry into the host cell. Therefore, the SARS-CoV-2 S protein is a key therapeutic target, and prevention and treatment of coronavirus disease 2019 (COVID-19) have focused on the development of neutralizing monoclonal antibodies (nAbs) that target this protein. In this review, we summarize the nAbs targeting SARS-CoV-2 proteins that have been developed to date, with a focus on the N-terminal domain and RBD of the S protein. We also describe the roles that binding affinity, neutralizing activity, and protection provided by these nAbs play in the prevention and treatment of COVID-19 and discuss the potential to improve nAb efficiency against multiple SARS-CoV-2 variants. This review provides important information for the development of effective nAbs with broad-spectrum activity against current and future SARS-CoV-2 strains.

BACKGROUND: Aortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1α) in aortic dissection was uncovered. METHODS: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies. FINDINGS: Macrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α. INTERPRETATION: This study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.