Coronavirus | Indian researchers find why variant with D614G mutation spread faster in Europe, U.S. but not East Asia

A study found that the variant with the D614G mutation introduced an additional cleavage site on the ACE-2 receptor for the SARS-CoV-2 virus to gain entry into cells

February 07, 2021 10:42 pm | Updated November 28, 2021 02:27 pm IST - CHENNAI

This handout illustration image obtained on February 27, 2020 courtesy of the National Institutes of Health taken with a scanning electron microscope shows SARS-CoV-2 (round blue objects) emerging from the surface of cells cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S.

This handout illustration image obtained on February 27, 2020 courtesy of the National Institutes of Health taken with a scanning electron microscope shows SARS-CoV-2 (round blue objects) emerging from the surface of cells cultured in the lab. SARS-CoV-2, also known as 2019-nCoV, is the virus that causes COVID-19. The virus shown was isolated from a patient in the U.S.

Kalyani-based scientists have found the biological mechanism behind the significantly faster spread of a variant with D614G mutation in Europe and North America but not in East Asia.

The variant with the D614G mutation seeded large outbreaks in Europe in early 2020 and subsequently dominated the outbreaks in North America, thereby largely replacing previously circulating lineages. The variant also spread worldwide.

A team led by Dr. Nidhan K. Biswas and Dr. Partha Majumdar from the National Institute of Biomedical Genomics, Kalyani found that the variant with the D614G mutation introduced an additional cleavage site on the ACE-2 receptor for the SARS-CoV-2 virus to gain entry into cells.

However, the presence of an additional cleavage site alone does not automatically lead to better efficiency in entering the cells. For the virus to enter the cells more efficiently, the additional cleavage site has to be opened. “The site is opened by a human protein called the neutrophil elastase. This protein is available in plenty in the lungs,” says Dr. Majumdar. “When the level of neutrophil elastase is high in an individual, the additional entry point created by the mutation opens up in a larger number of cells thus allowing more cells to be infected. Thus, the variant with the D614G mutation is able to spread better from one infected individual to another.”

 

But an excess amount of the protein neutrophil elastase can damage the lung tissue. Hence, the amount of neutrophil elastase produced is naturally kept under check by a protein called AAT (alpha1-antitrypsin). In other words, the AAT protein inhibits neutrophil elastase production.

However, some naturally-occurring mutations in the AAT-producing gene result in deficiency of the AAT protein, explains Dr. Majumdar. The AAT protein deficiency thus results in a higher level of neutrophil elastase and hence enhanced ability of the virus to infect human cells and spread among people.

“Compared with Asians, we found a large proportion of Caucasians in European countries and North America carry natural mutations in the gene that leads to deficiency in AAT production,” says Dr. Majumdar. “This is the reason why the variant spread widely in Europe and North America but not in Asia.” The results of the study are published in the journal Infection, Genetics and Evolution .

According to the paper, at 18.7 per 1,000 individuals, the AAT deficiency is the least in Poland while in Portugal as many as 75.9 per 1,000 individuals have AAT deficiency. Spain has the second highest deficiency of AAT protein at 67.3 per 1,000 individuals while it is 51.9 per 1,000 individuals in the case of France. Canada and the U.S. have 32.1 and 29 per 1,000 individuals with the protein deficiency, respectively.

In contrast, in the case of East Asia, Thailand has the highest at 19.9 per 1,000 individuals while it is just 8 and 5.4 per 1,000 individuals in Malaysia and South Korea, respectively.

“Even the lowest AAT protein deficiency level seen in the population in the U.S. and Poland is much more than the highest level seen in East Asia. This explains why the variant with the D614G mutation spread widely in Europe and North America and not in East Asia,” concludes Dr. Majumdar.

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