N501Y mutation in SARS-CoV-2 virus causes increased infectivity, disease severity in mice

Chinese researchers found N501Y mutation in a mouse-adapted SARS-CoV-2 virus strain. In the mouse model, the N501Y mutation was found to increase the binding affinity of the virus with the mouse ACE2 receptor. The mutation in the mouse-adapted strain also caused increased virulence.

In a preliminary report posted on December 19, Dr. Andrew Rambaut from the University of Edinburgh and others from the COVID-19 Genomics UK Consortium (COG-UK Consortium) say that the new variant has been spreading “rapidly” over the last four weeks. The COG-UK Consortium had analysed the genome data of SARS-CoV-2 virus and identified the variant.

Of the many mutations found in the variant, the scientists have pointed out that the N501Y mutation increases the transmissibility of the variant in humans. Though no studies have so far been done in humans to assess if the new variant increases the severity of COVID-19 disease, the Consortium researchers have pointed out to a study conducted in mice by Chinese researchers which shows that the N501Y mutation does indeed increase disease severity and infectivity.

In a paper published on September 25 in the journal Science, a team of researchers led by Dr. Shibo Jiang from the School of Basic Medical Sciences, Fudan University, Shanghai found that the N501Y mutation was associated with increased infectivity and virulence in the mouse model.

The Chinese researchers generated a SARS-CoV-2 mouse-adapted strain by using a human clinical isolate of the virus and serial passaging it in the respiratory tract of aged BALB/c mice. The resultant mouse-adapted strain exhibited a panel of adaptive mutations potentially associated with increased virulence. The N501Y mutation was among the five nucleotide mutations found in the mouse-adapted strain.

In the mouse model, the N501Y mutation was found to increase the binding affinity of the virus with the mouse ACE2 receptor. The mutation in the mouse-adapted strain also caused increased virulence.

“The increased virulence of SARS-CoV-2 [in the mouse-adapted strain] was likely attributed to the rapid emergence of N501Y substitution in the RBD of SARS-CoV-2 S protein,” they write. “The N501Y mutation seems to provide a more favourable interaction with mouse ACE2 for docking and entry, thus leading to the increased virulence phenotype in mice.”

Caution in interpretation

Dr. Gagandeep Kang, Professor of Microbiology at CMC Vellore, however, cautions that emergence of N501Y mutation has been seen on other occasions. According to her, the N501Y mutation in a strain that has been adapted to infect a mouse model cannot be compared with the N501Y mutation seen in the new variant infecting humans. And the severity of diseases caused by the mutation in the mouse model has no relevance to humans, she says.

“At this time, one can only say the mutation increases binding affinity in humans and hence increased transmissibility. Nothing can be said about disease severity,” says Dr. Kang.  

Published in The Hindu on December 23, 2020

One thought

  1. “There are several precedents for SARS-CoV-2 viruses arising with enhanced growth properties but no evidence that any of them cause worse disease. However, viruses with altered genomes may also increase in number simply because they arose in someone who happens to infect a lot of other people, perhaps in a crowded gathering, rather than because the virus has changed properties. “Experiments with purified viruses to test whether observed genetic changes result in altered properties of the virus will be needed to distinguish between these possibilities.  Use of such virological analyses is a vital tool for the further monitoring of potential virus evolution as the COVID-19 pandemic unfolds.”

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