key: cord-0937267-po0m1r0c
authors: Ruiz‐Medina, Blanca E.; Varela‐Ramirez, Armando; Kirken, Robert A.; Robles‐Escajeda, Elisa
title: The SARS‐CoV‐2 origin dilemma: Zoonotic transfer or laboratory leak?
date: 2021-11-22
journal: Bioessays
DOI: 10.1002/bies.202100189
sha: 3a4f3eae295ab535a05759ec27fb0ce37bb2390c
doc_id: 937267
cord_uid: po0m1r0c

The COVID‐19 pandemic is responsible for millions of deaths worldwide yet its origin remains unclear. Two potential scenarios of how infection of humans initially occurred include zoonotic transfer from wild animals and a leak of the pathogen from a research laboratory. The Wuhan wet markets where wild animals are sold represent a strong scenario for zoonotic transfer. However, isolation of SARS‐CoV‐2 or its immediate predecessor from wild animals in their natural environment has yet to be documented. Due to incomplete evidence for a zoonotic origin, a laboratory origin is plausible. The Wuhan Institute of Virology is at the epicenter of the pandemic and their work has included manipulation of wild‐type coronavirus to enable infection of human cells. Although stronger evidence supports the zoonotic transfer, inconclusive reports maintain the laboratory leak hypothesis alive. It is imperative to reach a factual conclusion to prevent future pandemics.

In the BioEssays. 2022;44:2100189.

wileyonlinelibrary.com/journal/bies 1 of 3 https://doi.org/10.1002/bies.202100189 same paper, the authors mention that "The possibility of the reemergence of SARS and other novel viruses from animals or laboratories and therefore the need for preparedness should not be ignored". [2] "Animals or laboratories" from this last sentence have become quite relevant in the current state of the ongoing WHO investigation, since both scenarios are plausible.

The scenario that the virus originated from wild animals either directly or via an intermediary host was presented early on during the pandemic by the Chinese virology research team of the Wuhan laboratory. Their argument is that the SARS-CoV-2, the causative agent for COVID-19 and other unknown viruses could be associated with everyday activities at the Wuhan wet markets. Live wild animals are sold for food or as pets and have no origin or quarantine certificate to guarantee hygiene. Stores at wet markets usually offer on-site butchering services with questionable sanitary practices, [3] where handling of contaminated products poses a risk of human infection. There is a low probability of a pathogen like a potential novel virus being transferred to humans if the infected animal is well-cooked before being consumed.

However, there could be a risk of transfer if a contaminated product is ingested raw or poorly cooked. In addition, humans can become infected by respiratory droplets or aerosols expelled by infected animals in the market. The coronavirus with the closest genome to the SARS-CoV-2 is RaTG13 (BtCoV/4991), which shares 96.2% sequence homology with the novel SARS-CoV-2 virus and was first identified in horseshoe bats (Rhinolophus affinis) at Yunnan, south China, [4] hence the idea of a natural transfer from animals to humans. It can be argued that the Huanan market in Wuhan was the source for the SARS- indicates that the first identified coronavirus-infected person never visited this market. [4] Additionally, no one has been able to find the SARS-CoV-2 or a sufficiently closely related virus in wild animals. [5, 6] Currently, humans are the dominant host species for the SARS-CoV-2. [9] Moreover, some lab-leak supporters affirm that a rare occurrence of a specific genetic codon sequence, CGG, one of the six codons for arginine, is a sign that the SARS-CoV-2 potentially originated in a laboratory. [10] A rare characteristic is the tandem arginine doublet, encoded by the lowfrequency CGG-CGG codons occurrence. Only 2 out of 42 arginines in the SARS-CoV-2 spike protein are encoded by the CGG codon. [10, 11] Moreover, those two arginines are located in the PRRA furin cleavage site. Surprisingly, the CGG-CGG codons in SARS-CoV-2 are not found in any of the furin cleavage sites in other viral proteins expressed by a wide range of viruses. [10, 11] However, the CGG codon is found in human coronaviruses. It encodes nearly 5% of the arginines in SARS-CoV-2 and close to 3% of the arginines in SARS-CoV. In addition, recent analyses have found recurring natural mutations in the viral spike protein that increase their fitness, infectivity, and ACE2 binding. [12] Furthermore, furin cleavage sites are commonly found in spike proteins of other coronavirus and the out-of-frame insertion of the one found in SARS-CoV-2 can be explained by straightforward evolutionary processes. [12] Similarly, the conservation of the CGG codon among the more than 2 million SARS-CoV-2 genomes sequenced to date indicates a natural functional role, or it would have been selected against throughout the evolution of the virus. [12] Some controversy also derived from a report published on Febru- incompatible with the observed data. [13] Regardless, reported viral transformations that occurred at the WIV are currently crucial and should be investigated because the origin of SARS-CoV-9 is elusive.

It is easy to assume that if the current COVID-19 pandemic was initiated from a zoonotic transmission incident, additional human infections would emerge from the same animal source, most likely occurring at the same geographic location or its surroundings. It is a matter of time to determine whether the SARS-CoV-2 variants evolving in humans, like the delta variant first identified in India, will affect wild animal species by reverse zoonosis; human → animals transmission.

At present, there is stronger evidence supporting a zoonotic transfer. However, lack of transparency has given way to maintain the laboratory leak hypothesis alive. Because of the implications, the two scenarios should remain on the table, and additional vigorous investigations are needed to reach a conclusion about the origin of SARS-CoV-2. More than likely, it will take some time before the knowledge of the origin of SARS-CoV-2 will be elucidated. Hence the faster we move to reach that conclusion, the better. The world is demanding and waiting for a factual answer because, once clarified, this knowledge can help prevent future pandemics.

COVID-19: The first documented coronavirus pandemic in history

Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection

Animal sales from Wuhan wet markets immediately prior to the COVID-19 pandemic

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Animal source of the coronavirus continues to elude scientists

The COVID lab-leak hypothesis: what scientists do and don't know

Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans

Difference in Receptor Usage between Severe Acute Respiratory Syndrome (SARS) Coronavirus and SARS-Like Coronavirus of Bat Origin

Should we discount the laboratory origin of COVID-19?

SARS-CoV-2 origin: An affair of codons

SARS-CoV-2 and the secret of the furin site

The origins of SARS-CoV-2: A critical review

Timing the SARS-CoV-2 index case in Hubei province

The authors declare no conflict of interest.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Elisa Robles-Escajeda https://orcid.org/0000-0002-0104-2857