Section 3: Mechanism of SARS-CoV-2 invasion into host cells (from DOI: 10.1016/j.clim.2020.108427)
From publication: "COVID-19 pathophysiology: A review" published as Clin. Immunol.; 2020 Apr 20 108427. DOI: https://doi.org/10.1016/j.clim.2020.108427
Section 3:Mechanism of SARS-CoV-2 invasion into host cells
Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses of ~30 kb. They infect a wide variety of host species. They are largely divided into four genera; alpha, beta, gamma, and delta based on their genomic structure. alpha and beta coronaviruses infect only mammals. Human coronaviruses such as 229E and NL63 are responsible for common cold and croup and belong to alpha coronavirus. In contrast, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 are classified to beta coronaviruses.
The life cycle of the virus with the host consists of the following 5 steps: attachment, penetration, biosynthesis, maturation and release. Once viruses bind to host receptors (attachment), they enter host cells through endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the nucleus for replication. Viral mRNA is used to make viral proteins (biosynthesis). Then, new viral particles are made (maturation) and released. Coronaviruses consist of four structural proteins; Spike (S), membrane (M), envelop (E) and nucleocapsid (N). Spike is composed of a transmembrane trimetric glycoprotein protruding from the viral surface, which determines the diversity of coronaviruses and host tropism. Spike comprises two functional subunits; S1 subunit is responsible for binding to the host cell receptor and S2 subunit is for the fusion of the viral and cellular membranes. Angiotensin converting enzyme 2 (ACE2) was identified as a functional receptor for SARS-CoV. Structural and functional analysis showed that the spike for SARS-CoV-2 also bound to ACE2. ACE2 expression was high in lung, heart, ileum, kidney and bladder. In lung, ACE2 was highly expressed on lung epithelial cells. Whether or not SARS-CoV-2 binds to an additional target needs further investigation. Following the binding of SARS-CoV-2 to the host protein, the spike protein undergoes protease cleavage. A two-step sequential protease cleavage to activate spike protein of SARS-CoV and MERS-CoV was proposed as a model, consisting of cleavage at the S1/S2 cleavage site for priming and a cleavage for activation at the S'2 site, a position adjacent to a fusion peptide within the S2 subunit. After the cleavage at the S1/S2 cleavage site, S1 and S2 subunits remain non-covalently bound and the distal S1 subunit contributes to the stabilization of the membrane-anchored S2 subunit at the prefusion state. Subsequent cleavage at the S'2 site presumably activates the spike for membrane fusion via irreversible, conformational changes. The coronavirus spike is unusual among viruses because a range of different proteases can cleave and activate it. The characteristics unique to SARS-CoV-2 among coronaviruses is the existence of furin cleavage site ("RPPA" sequence) at the S1/S2 site. The S1/S2 site of SARS-CoV-2 was entirely subjected to cleavage during biosynthesis in a drastic contrast to SARS-CoV spike, which was incorporated into assembly without cleavage. Although the S1/S2 site was also subjected to cleavage by other proteases such as transmembrane protease serine 2 (TMPRSS2) and cathepsin L, the ubiquitous expression of furin likely makes this virus very pathogenic.
