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SARS-CoV-2 Variants of Concerns Evolved to Modify Host Immune Response, Multiomics Study Shows

NEW YORK  — Using proteomic and genomic analyses, an international team of researchers has unraveled key mechanisms by which SARS-CoV-2 variants of concern (VOCs) evolved to evade the human immune system, leading to increased virus transmission.

The new finding could help develop prophylactic and therapeutic antiviral agents, which may help fight future pandemics.

In a study published in Cell on Thursday, researchers co-led by investigators from the University of California, San Francisco, described how VOCs such as Alpha, Beta, Gamma, and Delta showed convergent evolution by enhancing the same set of viral proteins to fight off the human immune response.

Most previous studies focused on mutations in the spike protein which the virus uses to latch onto the host cells for entry. However, the authors noted that VOCs have additional mutations in structural and accessory proteins, making the virus more transmissible. "Overall, our results highlight the plasticity of viral protein evolution and host-virus interactions, showing that viral point mutations, including noncoding changes, affect function," they wrote.

Further, they mentioned that all VOCs, some of which spread globally while others remained geographically constrained, evolved from the same early-lineage wave 1 virus, as shown in previous phylogenomic analyses.

For their new study, the researchers compared VOCs and wave 1 isolates, specifically from Australia and Europe. They collected VOC-infected cells from two independent infections in a lung cancer cell line. Cells were harvested 10 and 14 hours post-infection for bulk mRNA sequencing as well as for mass spectrometry-based abundance proteomics and phosphoproteomics.

Their findings showed several differences between the variants and the original isolates. Firstly, all VOCs, except Omicron BA.1, had altered viral gene expression during infection, ultimately suppressing interferon-stimulated genes. Secondly, all variants except Gamma showed evidence of modulating viral protein phosphorylation, notably on the nucleocapsid protein. Lastly, all VOCs had altered virus-host protein interactions. These factors helped the virus escape human immunity, especially the innate immune response.

The study strongly suggests that VOCs evolved to regulate pathways connected to innate immune and cytokine responses. "This likely reflects a strong selection imposed by the human innate immune system on the virus, whose ancestor likely adapted to evade innate immunity in a non-human species," they wrote.

The Omicron variant, however, was less effective at suppressing innate immune responses than the Alpha or Delta variants, even though subsequent Omicron lineages, particularly BA.5, enhanced this capacity by expressing higher levels of Orf6 and effectively suppressing interferon responses. The authors believe that Omicron, which successfully escaped widespread adaptive immune responses due to mutations in the spike protein, subsequently enhanced its innate immune evasion via upregulation of viral protein antagonists.

While the study was conducted in cell models, the author wrote that future studies could use a multiomics approach to study VOCs in animal models and human clinical samples to see if the same mechanisms are at play.