In order to develop effective strategies to diagnose, treat, and manage this disease, it is vital to understand exactly how SARS-CoV-2 enters human cells. The virus’ surface spike protein mediates SARS-CoV-2 entry into cells by binding to the ACE2 (Angiotensin-converting enzyme 2) receptor in humans through its receptor-binding domain and is proteolytically activated by human proteases. Cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry, thus making it more efficient in cell entry and infection.
In humans, the ACE2 receptor protein is present in many cell types (especially epithelial cells) and tissues including the nose, mouth, lungs, heart, blood vessels, kidneys, liver, and gastrointestinal tract. ACE2 assists in modulating the activities of a protein called angiotensin II (ANG II) which increases blood pressure and inflammation, thereby increasing damage to blood vessel linings and promotes various types of tissue injury. ACE2 converts ANG II to other molecules which effectively counteract the effects of ANG II, such as inflammation and cell death. When the SARS-CoV-2 virus binds to the ACE2 receptor, it prevents ACE2 from performing its normal function to regulate ANG II signaling. As such, ACE2 action is inhibited, removing the protective mechanism from ANG II signaling through increased availability of ANG II to injure tissues, especially in the lungs and heart. Figure 13.2.1 summarizes the transmission and life-cycle of SARS-CoV-2 causing COVID-19.
Take a look at the video below, How the Novel Coronavirus Infects a Cell: Science, Simplified, by Scripps Research (2020) on YouTube, describing how the novel coronavirus that causes COVID-19 enters the body and infects cells. Illustrated by a Scripps Research scientist, this installment of Science, Simplified gives an overview of the entire infection process.
- Figure 13.2.1 Fphar-11-00937-g001 by Colin D. Funk, Craig Laferrière, and Ali Ardakani (2020), CC BY 4.0, via Wikimedia Commons
Funk, C. D., Laferrière, C., Ardakani, A. (2020, June 19). A snapshot of the global race for vaccines targeting SARS-CoV-2 and the COVID-19 pandemic. Frontiers in Pharmacology 11. https://doi.org/10.3389/fphar.2020.00937
Scripps Research. (2020, July 13). How the novel coronavirus infects a cell (video file). YouTube. https://youtu.be/dA70ZdYhhCg
- Figure 13.2.1 Transmission and Life-Cycle of SARS-CoV-2 Causing COVID-19. SARS-CoV-2 is transmitted via respiratory droplets of infected cases to oral and respiratory mucosal cells. The virus, possessing a single-stranded RNA genome wrapped in nucleocapsid (N) protein and three major surface proteins: membrane (M), envelope (E) and Spike, replicates and passes to the lower airways potentially leading to severe pneumonia. The gateway to host cell entry (magnified view) is via Spike-converting enzyme 2 (ACE2) interaction with cleavage of Spike in the prefusion state by proteases TMPRSS-2/furin. A simplified depiction of the life cycle of the virus is shown along with potential immune responses elicited. [Back to Figure 13.2.1]