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Review
. 2021 May-Jun;35(3):1313-1326.
doi: 10.21873/invivo.12384. Epub 2021 Apr 28.

On the Origin of SARS-CoV-2: Did Cell Culture Experiments Lead to Increased Virulence of the Progenitor Virus for Humans?

Bernd Kaina  1
Affiliations
Review

On the Origin of SARS-CoV-2: Did Cell Culture Experiments Lead to Increased Virulence of the Progenitor Virus for Humans?

Bernd Kaina. In Vivo. 2021 May-Jun.

Abstract

We are currently in a rapidly expanding pandemic of the SARS-CoV-2 virus, which originated in the city of Wuhan in central China. The disease COVID-19 is now spread worldwide and has tremendous socio-economic consequences. The origin of the virus can be reconstructed through epidemiological studies and, even more so, from genome comparisons. How the evolution of the virus and the transition to humans might have happened is the subject of much speculation. It is considered certain that the virus is of animal origin and very likely passed from bats to humans in a zoonotic event. An intermediate host was postulated, but many SARS-like bat viruses have the ability to infect human cells directly, which has been shown experimentally by scientists in the Wuhan Institute of Virology using collected specimens containing virus material from horseshoe bats. The propagation of SARS-like bat viruses in cell culture allowed experiments aimed at increasing the infectivity of the virus and adaptation to human cells. This article summarizes the unique properties of SARS-CoV-2 and focusses on a specific sequence encoding the spike protein. Possible scenarios of virus evolution are discussed, with particular emphasis on the hypothesis that the virus could have emerged unintentionally through routine culture or gain-of-function experiments in a laboratory, where it was optimally adapted to human cells and caused cryptic infections among workers who finally spread the virus causing the pandemic.

Keywords: Corona virus; Covid-19; SARS-CoV-2; bat viruses; gain-of-function experiments; pandemic; review.

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Conflict of interest statement

The Author declares that there are no conflicts of interest related to this work.

Figures

Figure 1
Figure 1. Receptors and proteases required for entrance of SARS-CoV, SARS-CoV-2 and MERS-CoV viruses.
Figure 2
Figure 2. Sequence comparison of the spike protein of SARS-CoV-2 with other coronaviruses whose genome is very similar to that of SARS-CoV-2 (96.2% identity to the Bat-CoV RaTG13 strain isolated from the horseshoe bat; 79.5% identity to SARS-CoV and 91.0% identity to the virus isolated from the pangolin (27). (A) Genome of SARS-CoV-1. (B) S-protein. After binding to the ACE2 receptor, the spike protein is split into the S1 and S2 subunits. The S1 subunit mediates the binding to ACE2, the S2 subunit the efficient entry into the cell by membrane fusion. It is believed that after binding of the S protein to the ACE2 receptor, two (or even three) cleavage events are necessary for efficient entry into the cell. One is catalyzed by the protease TMPRSS2, the second by furin. (C) The furin cleavage site at the end of the Arg-Arg-Ala-Arg tetrapeptide is marked with an arrow (S1/S2). It is supposed that this cleavage occurs first, followed by cleavage of the S2' site (not shown) through TMPRSS2 (46). The nucleotide sequence that codes for the polybasic cleavage site (see text) rests on an insert that is unique for SARS-CoV-2. A similar insertion can be found in MERS-CoV. The amino acid sequence in the scheme is given using the 3-letter abbreviations in order to make it more understandable for nonbiochemists. Modified according to (39) and (16). (D) Sequence comparison of SARS-CoV-2 and MERS-CoV. Sequences are from NCBI database. The possible codon sequences for threonine and proline are given on the bottom of the figure.
Figure 3
Figure 3. Scenario according to which SARS-CoV-2 could have been evolved. The upper steps in the lab scenario of virus collection and experimentation are well documented in the literature.
See this image and copyright information in PMC

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