Syncytia Formation: A trademark of severe SARS-CoV-2 infection and a potential target for novel drug therapies

Abstract

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is characterized by its symptoms and complications primarily affecting the upper respiratory tract. Infected multinucleated syncytial pneumocytes have been observed in severe COVID-19 cases, alongside lung damage and lymphocytopenia. Syncytia formations allow the virus to evade the immune system, disseminate without cell exocytosis and cause cytopathicity and cell death. The mechanism of cell-cell fusion in SARS-CoV-2 infected cells is well documented as it relies on the same machinery as cell entry. The free spike (S) proteins localized at the cell membrane interact with ACE2 receptors and host proteases on neighbouring cells causing the cell membranes to fuse. However, the biological composition of these multinucleated cells is not well characterized.  Furthermore, how these multinucleated syncytia are interacting with their surrounding environment to cause the physical manifestations that are observed in COVID-19 patients is not yet fully understood. At present, there are no antivirals drug that have been developed or in use that directly target syncytia formation in SARS-CoV-2 and other syncytia-inducing viruses. This makes syncytia inhibition an overlooked yet promising area for new drug therapy development. Naturally, these shortcomings lead to the following questions that this article will focus upon 1) what the cellular and molecular composition of multinucleated syncytia is and how do they function biologically, and 2) how syncytia can be targeted to produce broad spectrum multidrug antivirals. A better understanding of the cellular composition and biological functions of syncytia can allow for a novel syncytia targeted antiviral that can prevent or reduce severe lung damage and other syncytial manifestations. Cell-cell fusion is not unique to SARS-CoV-2 as many other enveloped viruses such as respiratory syncytial virus (RSV) and Middle East respiratory syndrome related coronavirus (MERS-CoV) are known to induce syncytia in infected cells. Therefore, the impact of this research extends beyond SARS-CoV-2 and can pave the way for broad spectrum antivirals that target syncytia formation in other enveloped viruses. This could potentially reduce the burden that syncytia forming viruses have on public health, including the ongoing COVID-19 pandemic.