Virus News: Another SARS-CoV-2 Mutation T478K Seems To Be Spreading At Alarming Speeds Globally and Might Be The Next Dominant Mutation
: Italian researchers have identified a new SARS-CoV-2 mutation called T478K that is spreading at alarming speeds globally especially in Mexico and North America and might end up being a dominant mutation.
Numerous SARS-CoV-2 variants have emerged, posing a renewed threat to COVID-19 containment and to vaccine and drug efficacy. In this study, the researchers analyzed more than 820,000 SARS-CoV-2 genomic sequences deposited up to March 26, 2021 and identified a novel T478K mutation located on the SARS-CoV-2 Spike protein.
This mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 4,214 distinct cases.
The study team showed that the T478K mutation
has appeared and risen in frequency since January 2021, predominantly in Mexico and North America, but was also detected it in several European countries.
The study team warns that the new mutation seems to be spreading at alarming speeds and could become a dominant mutation globally.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.03.28.437369v1
The various SARS-CoV-2 variants of concern (VOCs) are characterized by mutations in the receptor-binding domain and more significant spike protein that enhance virulence by increasing the affinity of this region to the target ACE2 receptor found on the surface of cells, and could potentially better evade vaccine-generated antibodies that are specific to the wildtype spike protein.
The detailed genome of SARS-CoV-2 has been subject to continuous scrutiny since the early stages of the pandemic, and currently, nearly a million sequences have been publicly shared through various online databanks.
This has allowed a previously unheard-of degree of real-time analysis of the changing nature of the genome, which has been exploited in this study to identify a novel spike protein mutation that has risen in frequency among the population since early 2021.
The study team accessed 827,572 SARS-CoV-2 genomic sequences publically available from the global science initiative online databank as of March 26th, 2021, and compared them to the reference SARS-CoV-2 wildtype genome, uncovering nearly 17 million mutation events.
Upon translating these sequences into three-dimensional protein structures, the group identified novel mutation T478K in the spike protein ACE2 interaction complex, which existed in 4,214 COVID-19 patients.
Interestingly the variant B.1.1.222 was first detected in Mexico in April 2020, and currently the mutation T478K is present in around 65% of occurrences of this strain. Of the 4,214 samples discovered to bear this mutation by the group, 86% were of the B.1.1.222 variant. The remainder was of various distinct lineages, suggesting that this mutation has occurred in multiple distinct mutation events. This mutation was present in 38.1% of all cases in Mexico and 1.3% in the USA and was also detected infrequently in some European countries.&l
Alarmingly the frequency of the T478K mutation has risen exponentially since early 2021, similarly to another mutation in the spike protein: D614G, which the group also tracked over time. D614G was reported to emerge shortly before T478K and began to rise quickly in frequency in late 2020.
At present around 90% of SARS-CoV-2 genomes bear the D614G mutation, exhibiting the rapid rise to prominence of this mutation, which reportedly enhances virulence by promoting entry into the host cell.
However only around 2% of the total SARS-CoV-2 population bears the T478K mutation, according to this study, though if the mutation enhances virulence similarly then it may correspondingly rise to dominance.
This new T478K mutation constitutes the exchange of the non-charged amino acid threonine with the positively charged lysine at position 478 and roughly encompasses amino acids 350 to 550 of the SARS-CoV-2 spike protein. The exchange of amino acids at this position facilitates the presentation of a different electrostatic surface that can be further altered by co-occurring mutations, potentially interacting with receptors, antibodies, and drugs more strongly or weakly.
Also three other spike mutations were found to occur in parallel with T478K frequently: D614G, which represents one of the founding mutations of the B lineage and thus had co-occurrence of 99.8%; P681H, with 95.2% co-occurrence; and T732A, with 91.4% co-occurrence. How these amino acids interact to enhance the virulence of SARS-CoV-2 is currently unknown.
Also the study team highlights another group's results, where T478K and T478R mutations were observed to develop in SARS-CoV-2 treated with weakly neutralizing antibodies, suggesting that this mutation could aid in evading the immune response. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987023/
To date however there is not yet any clinical indication that T478K enhances virulence, however, the positioning of the mutant amino acid at the tip of the interaction point with ACE2 in association with the rapid rise in frequency recently observed in Mexico and the southern USA may indicate that this is the case. Mutations in this sensitive region of the spike protein often reduce affinity, and thus the fact that the variant is multiplying in the human population suggests survival validity.
This study underscores the importance of monitoring the occurrence and spread of SARS-CoV-2 mutants to better advice public policy and vaccine development.
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