L452R mutations may have triggered the emergence of several COVID-19 variants

Most of the recently risen coronavirus variants of interest or concern -- delta, kappa, epsilon, iota and lambda -- are universally carrying a mutation in amino acid L452 of the Spike protein that helps the virus bind to host cells.

Originally mutation L452R was discovered in early winter patient samples from California, first designated B.1.427 and B.1.429, and now known as the epsilon variant that underwent massive expansion across that state and is associated with many outbreaks.

In  some of the samples, the researchers found another L452R-carrying virus variant that emerged more recently than the epsilon It is circulating in California and has shown up in other states states. This variant caused the only recorded case of COVID-19 in apes by infecting a gorilla troop at the San Diego Zoo in early January.

Unlike the epsilon variant with four more mutations in the Spike protein,in that newer variant, (from the lineage B.1.232), the L452R mutation is the only one in the Spike protein that latches the virus onto cells to create a pathway to inject its genetic materials. The Spike proteins are what give the coronavirus its studded, crown-like appearance.

The researchers determined that the L452R mutation alone triggered the emergence of the two California variants.

Additional analyses have shown that a dozen coronavirus lineages carrying L452R mutations have arisen around the world, including the globally expanded delta and delta plus variants that originated in Inda, as well as their cousin variant Kappa. Another variant of concern, lambda, that originated in Peru and Chili, is carrying mutation L452Q. Other mutations in those variants were also acquired but were not as ominpresent as the L452 mutations

A rise in mutational variants, particularly in this part of the virus, is of public health concern, because of the potential that they might make the pandemic coronavirus more infective, more virulent or more able to escape protective antibodies, the scientists conducting the study noted.

The findings seem to suggest that mutations in L452R, in and of themselves, offer significant adaptive value to the pandemic corona virus. From a virus evolution standpoint, positive selection for this mutation somehow became strong only in the past several months. It is not certain why this happened, but it could have occurred as the virus adapts to growing population immunity or the containment measures.

How might the mutation provide a competitive advantage for the strains of virus that carry it? The mutation exchanges highly charged arginine or glutamine to replace the non-charged amino acid leucine-452, which is near the Spike protein area in direct contact with the ACE2 cell receptor for the coronavirus. This replacement is predicted to create a much stronger attachment of the virus to the human cells and also might allow it to avoid the neutralizing antibodies that try to interfere with this attachment.

However, although evidence for such assumptions is growing, additional research is necessary to determine the exact impact of the mutation on the virus structure and function. Additional work is also needed to see how it might affect the transmissibility and infectivity of the virus, how the immune system responds to the variant, and the course and severity of disease.

Because of the possibility of a powered-up version of the virus, the authors of the study say that the L452R mutations warrant more in-depth functional studies of how the mutation operates and how the different variants interplay.

The early findings from the study were published as a pre-print on BioRxiv in February. Updated, peer-reviewed findings were published August 11 in the Journal of Clinical Microbiology.

The senior author is Dr. Evgeni Sokurenko, professor of microbiology at the University of Washington School of Medicine.  An M.D./Ph.D. medical scientist, he explores how new strains of human pathogens emerge and spread, and how they acquire treatment resistance.  The lead author is Veronika Tchesnokova, also of the UW medical school's Department of Microbiology and ID Genomics, Inc.

A total of 570 positive test samples from April 2020 through February 2021 were included in this particular study.  They were gathered in Washington, California, Arizona, Colorado, Minnesota and Illinois.

Other agencies participating in this study were IEH Laboratories and Consulting Group, ID Genomics, The Antibiotic Resistance Monitoring, Analysis, and Diagnostic Alliance (ARMADA), and Kaiser Permanente Washington and its Research Institute.

The study was supported by the ARMADA Foundation, UW Department of Microbiology funds, and corporate funding by ID Genomics and IEH.