Gain-of-function and origin of Covid19

In nature, wild viruses adapted for transmission circulate in many animal species (bats, birds, primates…). Contamination of other animals, including humans, may occur by crossing of the species barrier. Genetic manipulations have been carried out on wild viruses to favor the species jumping and to increase of viral virulence. The aim was to identify the critical genes for pathogenicity. This has been mainly performed on potentially epidemic pathogens, as Myxovirus influenzae of avian flu and coronaviruses of SARS and MERS epidemics. These dangerous experiments were subject to a moratorium in the United States (2014–2017). Three years after the emergence of Covid-19, the origin of du SARS-CoV2 remains a mystery. Covid19 appeared in Wuhan, officially in December 2019, but probably during the autumn 2019. The virus was identified in January 2020. It belongs to the genus Betacoronavirus (subgenus Sarbecovirus). It was at once highly contagious. In addition, the primary isolates were genetically very homogeneous, differing only by two nucleotides without evidence for adaptive mutations. In addition, the Spike protein, a major virulence factor, has a furin site, not found in any other known sarbecovirus. Unlike the SARS and MERS epidemics, no intermediate host has been detected so far. Finally, no other outbreaks were reported at the beginning of the pandemic outside of Wuhan, contrary to what happened with the emergence of SARS (2002) and H7N9 avian influenza (2013). Today, there are two scenarios to explain the emergence of SARS-CoV2. Proponents of the natural origin argue that the bat virus might have directly infected humans, spreading silently at a low level in humans for years, without eliminating the existence of undetected intermediate hosts. This does not explain the origin in Wuhan, far away from the natural virus reservoirs. The furin site would have arisen spontaneously from other coronaviruses. The alternative scenario is that of a laboratory accident after gain-of-function manipulations from a SARS-like virus, or even the occurrence of a human contamination by a natural CoV virus grown on cells in Wuhan.

This article is an update to the Quarterly Medical Review (QMR) devoted to the history of modern pandemics. To access this QMR contents, please go here: https://www.sciencedirect.com/journal/la-presse-medicale/vol/51/issue/3