Study of the interactions established between the viral glycoproteins and their host receptors is of critical importance for a better understanding of virus entry into cells. The novel coronavirus SARS-CoV-2 entry into host cells is mediated by its spike glycoprotein (S-glycoprotein), and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we use atomic force microscopy to investigate the mechanisms by which the S-glycoprotein binds to the ACE2 receptor. We demonstrate, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as the binding interface within the S-glycoprotein with the ACE2 receptor and extract the kinetic and thermodynamic properties of this binding pocket. Altogether, these results provide a picture of the established interaction on living cells. Finally, we test several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.

Viral infection is an intricate process that requires the concerted action of both viral and host cell components. Entry of viruses into cells is initiated by interactions between viral proteins and their cell surface receptors. Despite recent progress, the molecular mechanisms underlying the multistep reovirus entry process are poorly understood. Using atomic force microscopy, we investigated how the reovirus σ1 attachment protein binds to both α-linked sialic acid (α-SA) and JAM-A cell-surface receptors. We discovered that initial σ1 binding to α-SA favors a strong multivalent anchorage to JAM-A. The enhanced JAM-A binding by virions following α-SA engagement is comparable to JAM-A binding by infectious subvirion particles (ISVPs) in the absence of α-SA. Since ISVPs have an extended σ1 conformer, this finding suggests that α-SA binding triggers a conformational change in σ1. These results provide new insights into the function of viral attachment proteins in the initiation of infection and open new avenues for the use of reoviruses as oncolytic agents.

In human and nonhuman primates, Shigella spp. cause bacillary dysentery by invading colon epithelium and promoting a strong inflammatory response; however, adult mice are resistant to oral Shigella infection. In this study, intraperitoneal challenge with virulent S. flexneri 2a (YSH6000) resulted in diarrhea and severe body weight loss in adult B6 mice. Of note, virulent S. flexneri 2a could invade and colonize not only systemic tissues but also the serosa and lamina propria region of the large intestine. In addition, epithelial shedding, barrier integrity, and goblet cell hyperplasia were found in the large intestine by 24 hours post-intraperitoneal Shigella infection. Of note, predominant expression of proinflammatory cytokines and chemokines were found in the large intestine after intraperitoneal challenge. Monocytes played a critical role in attenuating diarrhea and in providing protective efficacy against intraperitoneal Shigella infection. Most importantly, mice prevaccinated with attenuated S. flexneri 2a (SC602) strain were protected against intraperitoneal challenge with YSH6000. When taken together, these findings show that intraperitoneal challenge with virulent S. flexneri 2a can provoke bacillary dysentery and severe pathogenesis in adult mice. This model may be helpful for understanding the induction mechanism of bacillary dysentery and for evaluating Shigella vaccine candidates.

Study of virus entry into cells is of critical importance for a better understanding of the interactions established between the viral glycoproteins and their receptors at the cell surface and could help to develop novel antiviral strategies. The novel coronavirus (SARS-CoV-2) entry into host cells is mediated by the transmembrane spike glycoprotein (S-glycoprotein) and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we used atomic force microscopy to investigate the molecular mechanisms by which the S- glycoprotein binds to the ACE2 receptor. We demonstrated, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as a binding interface within the S- glycoprotein with the ACE2 receptor and we extracted the kinetic and thermodynamic properties of this binding pocket. Altogether, these results give a dynamic picture of the established interaction in physiologically relevant conditions. Finally, we identified and tested several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.