Elucidating the Entry and Fusion Landscape of Coronaviruses

The ongoing pandemic caused by SARS-CoV-2 has been unrivalled in history, with new variants appearing at a faster pace than what was known for any other virus before. The breakthroughs in vaccine development and therapeutic strategies have been unprecedented in the face of the pandemic, but with the virus mutating at such a fast rate, it is important to get a clear understanding of the entry and fusion of the virus. Angiotensin converting enzyme-2 (ACE2) is the known receptor for SARS-CoV-2 spike, which is primed for fusion by Transmembrane Serine Protease-2 (TMPRSS2). A recent report highlighted that another host factor, Neuropilin-1 (NRP1) can also interact with the spike and impact infectivity.

Through my research work in Singh P et. al. Cell Reports (2022), I have established that ACE2, NRP1 and TMPRSS2 can lead to fusion on their own when optimal conditions are provided, in the form of endosomal pH and endosomal calcium ion concentration. Even with this comprehension of the host factors interacting with SARS-CoV-2, its fusion to the host cell membrane is not well understood. Cell membrane lipids have been known to interact with viral glycoproteins. The glycolipid phosphatidylserine, which is a component of the inner leaflet of the plasma membrane, has been shown to have receptors which have important implications of viral infection. It has already been reported that PS exposure facilitates HIV (Human Immunodeficieny Virus) entry. For SARS-CoV-2, the role of the phospholipid phosphatidylserine (PS), has been an overlooked factor, even when there are a handful of reports that PS may regulate infectivity of the virus. A recent study has shown that blocking the calcium ion channel TMEM16, which is also involved in PS externalization, results in reduced syncytia formation, indicating reduced infection. It is important to pinpoint the conformational mechanisms through which PS is interacting with the SARS-CoV-2 virions. Delineating this interaction would also help in designing therapeutic strategies for the prevention of COVID infections.

The data that I have generated shows, for the first time, that fusion of SARS-CoV-2 virions is dependent on the PS present on the host cell membrane, and that their fusogenicity is greatly reduced if the PS on the host cell membrane is not available for interaction. My data is showing with direct evidence that fusion is PS-mediated, and this understanding will pave the road for development of novel therapeutic strategies for treatment of COVID, and other CoV infections.