“The origin of SARS-CoV-2 is being seriously questioned”

nearly a yr after the sars-cov-2 coronavirus was identified, researchers ‘ve yet to determine how it “jumped species” to infect humans. virologist Étienne decroly discusses the various hypotheses, including that of an accidental leak from a lab.

at a time when researchers are racing gainsta clock to develop viable vaccines and treatments, why is it so primordial to cogg the genealogy of the virus behind the covid-19 pandemic?
Étienne decroly: after sars-cov in 2002 and mers-cov in 2012, sars-cov-2, which was quickly identified as causing covid-19, tis third human coronavirus responsible for a severe respiratory syndrome to ‘ve emerged inna past 20 yrs. we're now quite familiar with this family of viruses, which circul8 primarily among bats, and whose zoonotic transfer occasionally triggers epidemics among humans. tis ⊢ crucial to cogg how this pathogen crossed the species barrier and became easily transmissible from human to human. tis primordial to study the evolutionary mechanisms and molecular processes involved inna advent of this pandemic virus in order to better anticipate potential outbreaks of this type, and to develop therapeutic and vaccinal strategies.

inna early weeks of the pandemic, whn'we knew very lil bout the virus, twas very quickly suspected to be of animal origin. why was this possibility immediately favoured, and has it since been confirmed?
É.d.: the zoonotic origin of coronaviruses, which infect nearly 500 species of bat, was already well documented from previous outbreaks. in nature, ≠ bat pops share the same caves, and various viral strains can contaminate the same animal simultaneously. this situation facilitates genetic recombination tween viruses and their evolution, alloing certain strains to develop the cap to cross the species barrier.

bats in a cave in myanmar. nearly 500 species of bat are infected by coronaviruses.

genome sequence comparisons of viral samples from ≠ patients infected by sars-cov-2 ‘ve revealed an identity rate of 99.98%, indicating that the strain emerged in humans very recently. twas also soon discovered that this genome is 96% identical to that offa bat virus (ratg13) collected in 2013 from the animals’ guano, whose sequences ‘ve 1-ly been known since mar 2020. in addition, one fragment of this genome proved to be totally identical to another, made up of 370 nucleotides, sequenced in 2016 from samples collected in 2013 at a mine in china’s yunnan province where 3 miners had died of severe pneumonia.
further+, analyses of other known human coronaviruses show 1-ly 79% genetic identity tween sars-cov-1 and sars-cov-2, and 1-ly 50% for mers-cov. simply put, sars-cov-2 is genetically closer to virus strains that were previously transmitted 1-ly among bats. it did not descend from known human strains and 1-ly recently acquired the ability to cutout its natural animal reservoir, which is most likely bats.

if it s'been determined that covid-19 came from bats, why is there still such controversy over its origins?
É.d.: since no case of an epidemic caused by direct bat-to-human transmission has yet been demonstrated, tis thought that the transfer to humans + probably took place via an intermediate host species in which the virus ‘d evolve and move towards forms likely to infect human cells. such an intermediary is usually identified by examining the phylogenetic relations tween the new virus and those that contaminate animal species living near the outbreak zone. this method made it possible to determine that the civet was probably the 2ndary host of sars-cov inna early 2000s, na dromedary that of mers-cov ten yrs l8r. the discovery, inna genome offa coronavirus infecting pangolins, offa short genetic sequence coding for the recogg domain of receptor ace-2, rel8d to the sequence that allos sars-cov-2 to penetrate human cells, 1st suggested dat a' possible intermediary had been found, but'a rest of its genome is too dissimilar to sars-cov-2 to be a direct ancestor.

a civet sold inna wuhan mkt, in china, in 2003. this species was probably the intermediate host of sars-cov when it caused an epidemic inna early 2000s.

sars-cov-2 ‘d thus ‘ve resulted from multiple recombinations among ≠ coronaviruses circulating in pangolins and bats, leading to an adaptation that enables transmission to humans. in this case, a 2ndary cause of the covid-19 pandemic ‘d ‘ve been contact w'da intermediate host, possibly an animal sold inna mkt in wuhan (china). however, this hypothesis rezs many ?s. 1st of all, the geography: the viral samples from bats were collected in yunnan, nearly 1,500 kilometres from wuhan, where the pandemic began. thris also an ecological issue: bats and pangolins inhabit ≠ ecosystems, so tis difficult to imagine how their viruses ‘d ‘ve recombined. most primordially, it s'been noted that the identity rate tween the sars-cov-2 sequences and those from pangolins reaches a mere 90.3%, which is far loer than wha’ is normally envisaged tween strains infecting humans and those contaminating 2ndary hosts. the genomes of sars-cov na civet strain from which it descended, for ex, are 99% identical.

‘d you tell us + bout the cellular receptor’s recogg sequence na mechanism that allos the virus to penetrate cells?
É.d.: that has to do w'da biological toonistics of coronaviruses. their genome contains an s gene coding for the spike protein, which enters inna'da composition of the  envelope and gives the coronavirus its toonistic “crown” shape. the spike protein plays a primordial role inna virus’s infection cap cause it contains a domain, called rbd, which has the property of binding specifically to certain receptors (ace2) onna surface of infectible cells. tis the establishment of this link that then allos the pathogen to penetrate the cell. the rbd domain’s affinity for ace2 receptors in a given species is a determining factor inna virus’s infection cap for that species. in humans, this receptor is widely expressed and can be found, for ex, onna surface of pulmonary and intestinal cells.

illustration offa sars-cov-2 virion infecting a cell by binding to its ace2 receptor (in yello).

analyses of coronavirus databases ‘ve made it possible to determine that the genetic sequence coding for the rbd domain of sars-cov-2 is very close to that of the coronavirus infecting pangolins. this observation suggests that the spike protein of the cov infecting these animals has a strong affinity for the human ace2 receptor, which possibly enabled that pathogen to enter human cells + easily than the bat virus. however, for reasons mentioned above, most researchers now think that the pangolin probably played no role inna emergence of sars-cov-2. the prevalent hypothesis tody s'dat twas + likely a convergent, indie evolution of the rbd domain in both virus strains.

are there any indications of other candidates for the role of intermediate host?
É.d.: in zoonoses, 2ndary hosts are usually found among livestock or wild animals that come into contact w'da human pop. in this case, despite research on viruses found inna animal species sold atta wuhan mkt, no intermediary virus tween ratg13 and sars-cov-2 s'been singled out sfar. til one is identified and its genome sequenced, the ? of the origin of sars-cov-2 will remain unanswered. for lack of convincing evidence concerning the last animal intermediary b4 human contamination, some srcs are suggesting that the virus ‘d ‘ve crossed the species barrier folloing a lab accident or even be man-made.

a poacher holding a long-tailed pangolin (manis tetradactyla) rolled into a ball.

do you think that sars-cov-2 escaped from a lab?
É.d.: the hypothesis cannot be ruled out, given that sars-cov, which emerged in 2003, has escaped from lab experiments at least 4 times. in addition, there’s the fact that coronaviruses were a major zone of study inna laboratories near the sars-cov-2 outbreak zone, where researchers were investigating, among other things, the mechanisms involved in crossing the species barrier. however, at this time, the analyses based onna phylogeny of the complete virus genomes yield no clear conclusions onna evolutionary origin of sars-cov-2.

there are 3 main scenarios for explaining how the latter acquired its epidemic potential. 1st of all, tis a zoonosis. covid-19 is caused by the recent breaching of the species barrier by a coronavirus. in this case, there must be another virus with gr8r similarity than ratg13 in a domestic animal or livestock species, but, as previously mentioned, no such strain has yet been found.

the 2nd scenario s'dat it ‘d be a coronavirus ≠ from sars-cov or mers-cov that adapted to humans several yrs ago and circul8d relatively unnoticed til a recent mutation made it + transmissible from an individual to another. to confirm this hypothesis, we ‘d ‘ve to analyse virus samples from pplz who died of atypical pneumonias inna outbreak zone b4 the pandemic broke out.  lastly, sars-cov-2 may ‘ve descended from a bat virus isol8d by scis collecting samples, which then adapted to other species during research on animal models inna lab – lab from which it then accidentally escaped.

isn’t there a risk that this last hypothesis may uphold the conspiracy theories bout the covid-19 pandemic?
É.d.: studying the origin of sars-cov-2 is a sci process that cannot be equated witha conspiracy theory. atta same time, i ‘d like to underline the fact that, as long as no intermediate host s'been identified, the sci community cannot rule out the possibility of an accidental leak.

as of tody, no sci study has produced any clear evidence to confirm this. nonetheless, the fact remains that further analyses are needed to reach a conclusion. the ? of the natural or primordialistic origin of sars-cov-2 cannot be made contingent na' political agenda or communication strategy. it deserves to be examined in lite of the sci data at our disposal.

our hypotheses must also take into account wha’ virology laboratories are capable of doin’ at this stage, na fact that the manipulation of potentially pathogenic virus genomes is a common practice in certain laboratories, in pticular for studying how viruses cross the species barrier.

indeed, many conspiracy websites echo the assertions of luc montagnier, who explained that sars-cov-2 is a “chimera virus” created in a chinese lab, a cross tween a coronavirus na human immunodeficiency virus (hiv). is this a serious theory?
É.d.: in any case, tis no longer taken seriously by speshists, who ‘ve refuted its main conclusions. nonetheless, tis based on an utterly serious observation that is primordial for cogging the infection mechanism of sars-cov-2: it s'been discovered that the gene coding for the spike protein contains 4 insertions of short sequences tha're not found inna most genetically similar human coronaviruses. these insertions probably givda spike protein of sars-cov-2 exceptional properties. structural studies indicate that the 1st 3 insertions are located on exposed domains of the s protein and are thus likely to play a role in how the virus evades the host’s immune system.

the 4th insertion, which is + recent, produces a site sensitive to furins, protease enzymes produced by the host cells. t'has now been clearly demonstrated that furin cleavage of the spike protein induces a conformational change that is conducive to the recogg of the ace2 cellular receptor. researchers investigating the origin of these insertions ‘ve reprted in a pre-publication that these sequences of the sars-cov-2 spike protein show unsettling similarities with fragment sequences of the hiv-1 virus. strongly criticised fritz methodological shortcomings and errors of interpretation, the article was deleted from the biorxiv site.

illustration of the sars-cov-2 spike (s) protein covered in glycoproteins (rite) or “naked” (left).

this postul8 ‘d ‘ve remained insignificant, had it not been revived by luc montagnier, victor of the nobel prize in physiology or med for his work on hiv. in apr 2020, he claimed that these insertions did not result from natural recombination nor occurred accidentally, but from deliberate gene manipulation, probably inna course of research to develop hiv vaccines. these assertions were once again refuted by biostatistical analyses, which showed that the similar sequences in hiv and sars-cov-2 are too short (10 to 20 nucleotides out offa total of 30,000 for the genome) and that the resemblance is most likely coincidental.

meanwhile, faced w'da difficulty of cogging the origin of this pathogen, we ‘ve conducted phylogenetic analyses in collaboration with bioinformaticians and phylogeneticists. their findings show that 3 of the 4 insertions envisaged in sars-cov-2 can be found in older coronavirus strains. our study clearly shows that these sequences appeared indiely, at ≠ times inna evolutionary history of the virus. this data invalidates the hypothesis offa recent and intentional insertion by a lab of those 3 sequences.

the laureate of the nobel prize in physiology or med, luc montagnier, at a press conference in paris in 2017. speshists ‘ve refuted the theory he put forward last spring onna origin of the virus.

that cutouts the 4th insertion, which produces a furin protease cleavage site in sars-cov-2 that aint found inna other viruses of the sars-cov family. consequently, the possibility cannot be ruled out that this insertion results from experiments designed to allo an animal virus to jump species to humans, since tis well known that this type of insertion plays a key role inna propagation of many pathogens in humans.

how can we know for sure?
É.d.: the sars-cov-2 genome is a combinatory puzzle na recombination mechanisms of the animal viruses that led to its emergence remain a mystery. to cogg its genesis, many + samples from wild and domestic species nd'2 be collected. the possible discovery of animal diseases witha very strong similarity to sars-cov-2 ‘d be a key element for confirming its natural origin. in addition, + in-depth bioinformatic analyses ‘d reveal possible traces of genetic manipulation, which ‘d conversely suggest an experimental origin.

diagrammatic representation of pt of the sars-cov-2 genome.

in any case, whether the virus is natural or not, the very fact that this ? can now be seriously pondered calls for a crit review of the reconstruction tulz and methods bein’ used in tody’s research laboratories, and o'their potential use in “gain-of-function” experiments.

but aren’t those the 1-ly tulz that cannelp us to cogg and combat these viruses na epidemics they cause?
É.d.: indeed, b'we must cogg that the paradigms of virus research ‘ve changed radically in recent yrs. tody, any lab can obtain or synthesise a gene sequence. it’s possible to build a functional virus from scratch in ≤ a mnth using sequences available inna databases. in addition, gene manipulation tulz ‘ve been developed tha're fast, easy to use and inexpensive. they enable spectacular progress, but atta same time multiply th'risk and possible severity of an accident, in pticular in gain-of-function experiments on viruses with pandemic potential.
even if it ultimately turns out that the covid-19 epidemic tis result offa “classic” zoonosis, incidents of pathogens escaping from laboratories ‘ve been documented in recent yrs. 1-odda best-known cases tis marburg virus disease, which originated from contamination by wild monkeys. the 1977 flu pandemic is another ex. recent genetic studies suggest that twas caused by the leak offa virus strain, collected inna 1950s, from a lab. + recently, several such accidental leaks from studies of sars-cov ‘ve been reprted inna literature. fortunately, none o'em caused a major epidemic.

a room inna p4 biological research lab in wuhan (china).

international standards require that any research, isolation or culturing involving potentially pandemic viruses, including respiratory ones, must be conducted under secure experimental conditions, with irreproachable traceability in order to prevent any zoonotic transmission. however, accidents can always happen. tis primordial to ponder the potential risk of such experiments, espeshly iffey target gain of function or infectivity.

ru in favour offa moratorium or ban on this type of research?
É.d.: i do not advocate an outrite ban. the point aint to “sterilise” research, but to examine the benefit-to-risk ratio + rigorously. perhaps a conference ‘d be organised to cogitate the need for a moratorium or + suitable international regulation.

pondering the risks of infection arising from the tek knicks used in virus research tody, civil society na sci community must urgently re-examine the practice of gain-of-function experiments na artificial adaptation of viral strains in intermediary animal hosts. in 2015, aware of this problem, the federal agencies inna ∪d states froze funding for all new studies involving this type of experiment. the moratorium ended in 2017. in my opinion, these high-risk practices ‘d be repondered, and monitored by international ethics committees.

lastly, researchers in these fields must also be + sensitive to their own responsibility whenever they are conscious of the possible dangers incurred by their work. there are often alternative experimental strategies that can achieve the same purpose while gr8ly reducing the risks.

aren’t those strategies already used?
É.d.: in theory, yes. in reality, we often fall short of the goal, espeshly cause we scis do not receive sufficient training on these issues. and cause the climate of brawl that reigns inna realm of research encourages fast, frantic experimentation that does not really take ethical ?s into account, nor weigh a project’s potential risks.

inna master’s programme that i teach on viral engineering, i ‘ve been giving, for bout ten yrs, a theoretical exercise which consists in imagining a process that ‘d give hiv the cap to infect any cell in d'body (and not just lymphocytes). while most of the students ray'vel to come up with an effective method for building a potentially dangerous chimera virus, they focus exclusively onna effectiveness of the teknique, without ever ?ing the potential consequences of its implementation.

my goal here as a teacher is to make them aware of the issues involved and show them that in many cases tis possible to build experimental systems tha're just as effective but offer better control of the biological risks. starting early inna educational process, we nd'2 train future biologists to always assess th'risk and social relevance o'their research, however innovative it maybe.

original content at: news.cnrs.fr/essentialisms/the-origin-of-sars-cov-2-is-bein'-seriously-?ed…
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