The SARS-CoV-2 Life Cycle

Like other coronaviruses, the genome of SARS-CoV-2 contains ten or more open reading frames (ORFs) encoding some 29 proteins. Roughly two thirds of the viral RNA are contained within the first two, called ORF1a and ORF1b. [1] These are translated into two large non-structural polypeptides (NSPS) that are then cleaved into multiple smaller NSPS. [2] Based on the functions of their SARS-CoV and MERS-CoV homologs, the NSPS are thought to hijack the membrane structures of the host rough endoplasmic reticulum, rearranging them into double-membrane vesicles (DMVs) wherein viral transcription takes place. [3] The other one-third of the viral genome contains ORFs for the 4 principal structural proteins: spike (S-protein), nucleocapsid (N-protein), envelope (E-protein), and membrane (M-protein), along with several accessory proteins with as yet unclear functions.

Structure of the SAR-CoV-2 virus
Structure of the SARS-CoV-2 virus

The S-protein represents the key to viral entry into the host cell. First, the virus’s S-protein’s receptor binding domain (RBD) on the S1 domain attaches to the cell surface protein angiotensin-converting enzyme (ACE2). Subsequently, the S-protein’s S2 domain engages the type II transmembrane protease (TMPRSS2) to accomplish a crucial cleavage step known as priming, which allows fusion of the S-protein with the cell membrane. [4]

Inside the cell, the virus converts intracellular membrane structures into DMVs which serve as factories for viral RNA replication, transcription, and virus particle assembly. [5] As the viral particles are built, nascent N-proteins insert into the host membrane, forming a nucleocapsid structure. Finally, the virus particle-containing vesicles fuse with the plasma membrane and mature virions are released. [1]

  1. Li X, et al. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis (2020).
  2. Kim D, et al. The architecture of SARS-CoV-2 transcriptome. Cell (2020).
  3. Perlman S, and Jason Netland. Coronaviruses post-SARS: update on replication and pathogenesis. Nature reviews microbiology 7.6 (2009): 439-450.
  4. Hoffmann K, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell (2020).
  5. Knoops K, et al. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS biology 6.9 (2008).

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