SARS-CoV-2 Research: Study Finds That Mutations On ORF3a Determines SARS-CoV-2 Viral Fitness Through Modulation Of Lipid Droplets
: A new study by scientists from Shanghai Jiao Tong University School of Medicine-China, University of Alberta-Canada, University of California-USA and Shanghai University of Traditional Medicine, Shanghai, China has found that that mutations on ORF3a determines SARS-CoV-2 viral fitness through modulation of lipid droplets.
Typically, SARS-CoV-2 infection leads to the accumulation of lipid droplet (LD), the central hubs of the lipid metabolism, in vitro or in type II pneumocytes and monocytes from COVID-19 patients and blockage of LD formation by specific inhibitors impedes SARS-CoV-2 replication.
The study team showed that ORF3a is necessary and sufficient to trigger LD accumulation during SARS-CoV-2 infection, leading to efficient virus replication.
Though highly mutated during evolution, ORF3a-mediated LD modulation is conserved in most SARS-CoV-2 variants except the Beta strain and is a major difference between SARS-CoV and SARS-CoV-2 that depends on the genetic variations on the amino acid position 171, 193, and 219 of ORF3a.
Interestingly, T223I substitution in recent Omicron strains (BA.2-BF.8) impairs ORF3a-Vps39 association and LD accumulation, leading to less efficient replication and potentially contributing to lower pathogenesis of the Omicron strains.
The study findings characterized how SARS-CoV-2 modulates cellular lipid homeostasis to benefit its replication during virus evolution, making ORF3a-LD axis a promising drug target for the treatment of COVID-19.
The study findings were published in the peer reviewed Journal of Medical Virology.
The study is the first to investigate the genetic diversity of the ORF3a gene among different SARS-CoV-2 strains and its impact on virus fitness. The ORF3a gene is involved in viral replication and pathogenesis, but its role in lipid metabolism and virus-host interactions is not well understood.
The study team used bioinformatics tools and laboratory experiments to analyze the genetic variation of the ORF3a gene and its impact on virus fitness. They found that genetic diversity in the ORF3a gene was associated with differences in the ability of the virus to form lipid droplets, which are essential for viral replication and assembly.
Most importantly, study team found that a single nucleotide polymorphism (SNP) in the ORF3a gene, which results in an amino acid change from serine to asparagine, was associated with increased lipid droplet formation and virus fitness.
The asparagine variant of ORF3a was more prevalent in SARS-CoV-2 strains isolated in the early stages of the pandemic, suggesting that it may have conferred a selective advantage to the virus during its initial spread.
The study team also found that the ORF3a protein interacts with host proteins involved in lipid metabolism, suggesting that it may modulate lipid droplet formation and virus fitness through this mechanism.
The research's findings provide new insights into the genetic diversity of SARS-CoV-2 and its impact on virus-host interactions.
The study team notes th
at the results have important implications for the development of antiviral therapies and vaccines that target the ORF3a protein or its interactions with host proteins.
The corresponding author of the study, Dr Qiming Liang from Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China notes that the study highlights the importance of genetic diversity in virus evolution and adaptation.
He told Thailand Medical News, "Our SARS-CoV-2 Research
shows that genetic variation in the ORF3a gene can have a significant impact on virus fitness and host interactions. This highlights the importance of understanding the genetic diversity of SARS-CoV-2 and its potential impact on the development of antiviral therapies and vaccines."
The study team suggests that targeting the ORF3a protein or its interactions with host proteins may be a promising approach for developing new treatments or vaccines against COVID-19.
The findings also highlight the importance of monitoring genetic diversity in SARS-CoV-2 and other viral pathogens, as genetic variation can play a critical role in virus evolution, pathogenesis, and transmission. As new SARS-CoV-2 variants continue to emerge, it will be important to monitor the genetic diversity of the virus and its potential impact on public health.
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