Deletion mutations of SARS-CoV-2 may have attenuated infectivity in some strains

Caused by the severe acute respiratory syndrome agent coronavirus 2 (SARS-CoV-2), the 2019 coronavirus disease (COVID-19) pandemic has reached over 191 countries and infected more than 63.98 million people. Scientists around the world are racing to better understand the virus, how it is transmitted and how it affects the body.

A team of researchers from the University of Hong Kong has identified a panel of SARS-CoV-2 variants, called Del-mut, which contains a deletion at the S1 / S2 junction. After studying one of the eliminated variants in animal models, they found that Del-mut-1 is attenuated in its ability to cause disease or pathological changes.

The emergence of SARS-CoV-2

The SARS-CoV-2 pathogen was first detected in the city of Wuhan, China in December 2019. Since then, it has spread rapidly around the world, killing over 1,481 million people.

The exact origin of the virus remains elusive. However, the presence of a distinct motif at the S1 / S2 junction suggests the possible acquisition of cleavage sites in the spike protein that promoted zoonosis or inter-species transmission.

Zoonosis occurs when pathogens of animal origin jump onto human hosts and cause infection. The virus then adapts to the human body and begins transmission between human hosts.

The virus’s spike protein – the protruding spikes that line its envelope – binds to human cell angiotensin converting enzyme 2 (ACE2) receptor, which acts as a cellular gateway for viral entry.

Genetic analysis of the virus revealed a potential genetic link between SARS-CoV-2 and coronaviruses identified in bats in Yunnan, China. However, there is still no direct ancestral virus or intermediate host for the cross-transmission of SARS-CoV-2 to humans.

Meanwhile, scientists suggest that efficient human-to-human transmission appears to have occurred as soon as the SARS-CoV-2 outbreak was detected. The dynamics of viral spread and host response during the early stage of disease onset show that the virus has a unique human transmission capacity.

I study

In the study, published in the journal Emerging microbes and infections, the researchers found a number of variants containing deletions of 15-30 bp (Del-mut) or point mutations at the S1 / S2 junction. They also looked at the original clinical specimen where the isolate was obtained, and 26 other SARS-CoV-2 positive clinical specimens failed to detect these variants.

To investigate further, the team inoculated the hamsters with the virus and found that one of the variants, Del-mut-1, which carries a deletion of ten amino acids, does not cause weight loss or more severe pathological changes in the lungs, which it is related to wild type virus infection.

The team noted that the unique cleavage motif that promotes SARS-CoV-2 infection in humans could be under severe selective pressure as replication in permissive Vero-E6 cells leads to the loss of this adaptive function. This supports the claim that the acquired function of S1 / S2 junction insertion is only needed for non-permissive replication.

Virus replication in the lung tissues of hamsters infected with the WT or Del-mut-1 SARS-CoV-2 virus. (A) Indirect immunofluorescence test with antibodies against SARS-CoV-2 virus protein N (green). Blue: DAPI staining of cell nuclei. B: bronchiole, V: blood vessel. (B) Titration of the virus by plaque assay of lung and tracheal tissues collected on days 2 and 4 after infection. Error bars represent mean ± sd (n = 2 per group for each timepoint) Scale bar, 200 µm, dpi: days after infection.

Further investigation is needed to determine whether the outstanding transmissibility of SARS-CoV-2 is related to the acquired function of the S1 / S2 junction insertion. Currently, circulating human coronaviruses, such as the one that cause the common cold, do not contain a primary motif at the S1 / S2 junction.

Therefore, if SARS-CoV-2 is to become a complete human virus, one of the Del-mut variants could be the final form of the virus. Because the Del-mut-1 variant does not cause severe disease in animals, its attenuated form can be used to perform drug screening research or functional studies in laboratories where a high-level biosecurity facility is not available.

“One of the most pressing needs in response to COVID-19 is the development of an effective vaccine to contain the ongoing pandemic and in preparation for the long-term prevalence of the SARS-CoV-2 virus. The safety and vaccination potential of the Del – Mut variants should also be explored, “the team concluded in the study.

So far, ten candidate vaccines are in the final stages of human testing and two are awaiting regulatory approval. With new information about the virus continually emerging, scientists need to see it as a basis for developing new effective and safe vaccines to fight COVID-19.