also claimed that the RBD of SARS-CoV-2 might have been engineered by using a RBD domain with a higher affinity for the human ACE2 receptor and by inserting the RRAR furin cleavage site downstream of the RBD, making the virus more infectious in human cells. Before retraction of their manuscript, Pradhan et al. Other hypotheses were based on the construction of infectious recombinant SARS-CoV capable to replicate in mammalian cell lines or animal models ( Becker et al., 2008, Menachery et al., 2020). Furthermore, the four insertions identified in SARS-CoV-2 occurred independently at different times of coronaviruses diversification ( Sallard et al., 2020). This article has since then been retracted. This hypothesis was rebutted by bioinformatic analyses showing that the similarity of those short putative HIV insertions was insufficient to support a common ancestral origin of the sequences ( Liu et al., 2020c Xiao et al., 2020b). The first hypothesis is that of a man-made virus raised first by Pradhan and colleagues who claimed to have observed the presence of HIV sequences in SARS-CoV-2, before retraction of the manuscript and then by Perez and Montagnier (2020). The origin of SARS-Cov-2 is still passionately debated since it makes ground for geopolitical confrontations and conspiracy theories besides scientific ones. However, two major issues remain unresolved: i) the origin of the virus and ii) the initial route of infection leading to the pandemic.Ģ.1. A parallel ‘digital pandemic’ (overcommunication on more or less probable ‘scientific hypothesis’) developed on social networks, bringing opinions and conspiracy theories, generating anxiety and irrational behavior. A rush for scientific publications occurred with 111,726 Pubmed references for “COVID-19” as per March 11, 2021. This leads to a key feature of COVID-19: it is the very first pandemic to occur in our hyper connected society. Although contradicted ( Frutos et al., 2020a, Li et al., 2020, Liu et al., 2020b) the pangolin hypothesis was repeated so many times in scientific papers and on social networks that was taken for a truth even within part of the scientific community. The in-silico modeling of SARS-CoV-2 spike and ACE2 receptor highlighted a potential affinity between SARS-CoV-2 spike and pangolin ACE2, but it was not limited to this species ( Liu et al., 2020a Luan et al., 2020 Shi et al., 2020). Snakes were first proposed ( Ji et al., 2020) and after rejection of the hypothesis ( Zhang et al., 2020a Callaway and Cyranoski, 2020), the Malayan or Sunda pangolin, Manis javanica, was in turn designated as intermediate host ( Xiao et al., 2020a Zhang et al., 2020b). Since the spillover model postulates that an animal reservoir must be at the origin of the zoonosis ( Plowright et al., 2017), a hunt for this intermediary host began using in-silico studies. Beside laboratory accidents, there is no evidence of direct transmission of bat-CoV to humans ( Heymann et al., 2004 Watts, 2004a Webster, 2004 WHO, 2004). Since then, viruses closely related SARS-CoV-2 have been described in Rhinolophus shameli bats caught in 2010 in Cambodia ( Hul et al., 2021) and in Rhinolophus acuminatus bats from Thailand ( Wacharapluesadee et al., 2021). Another batCoV sequence, RmYN02, was identified also in Yunnan in the horseshoe bat Rhinolophus malayanus ( Zhou et al., 2020b). RaTG13, the closest to SARS-CoV-2 genome, was isolated in 2016 from an anal sample of a horseshoe bat ( Rhinolophus affinis) from Yunnan ( Zhou et al., 2020a Ge et al., 2016). Following the description of the first clinical cases ( Huang et al., 2020 Lu et al., 2020), SARS-CoV-2 was rapidly sequenced ( Zhu et al., 2020) and linked to bats CoV belonging to the lineage b of betacoronavirus ( Zhou et al., 2020a). COVID-19 is considered to have started at the Huanan Seafood Wholesale Market (HSWM) in Wuhan on Decem( Huang et al., 2020 WHO, 2020).
If the human-to-human transmission of SARS-CoV-2 has been rapidly demonstrated ( Huang et al., 2020 Kucharski et al., 2020), explaining the magnitude of the pandemic, the origin of the virus remains elusive.
Since the beginning of the COVID-19 pandemic in December 2019, a major issue has been the origin of the virus and how it was transmitted to humans.