The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission 1 , 2 . Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant 3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection 4 . The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants. The SARS-CoV-2 Alpha variant suppresses innate immune responses more effectively than isolates of first-wave SARS-CoV-2, and this is a result of mutations outside of the spike coding region that lead to upregulation of viral innate immune antagonists.
【저자키워드】 SARS-CoV-2, Systems biology, 【초록키워드】 proteomics, Mutation, innate immune response, Human, variant, SARS-CoV-2 variant, variants of concern, Delta, Transmission, Proteins, omicron, variants, Spike protein, nucleocapsid protein, airway, RNA, Replication, Protein, Viral, SARS-CoV-2 variants, B.1.1.7, viral replication, immune responses, RNA sequencing, Phosphorylation, Alpha, epithelial cells, ORF6, Orf9b, Alpha variant, Phosphoproteomics, adaptation, expression, association, innate immune, Interaction, MAVS, isolates, airway epithelial cells, lead, mitochondrial, observation, characterization, Duration of infection, Activation, coding region, effort, upregulation, antagonists, human-to-human transmission, protein level, protein levels, viral adaptation, innate immune responses, regulatory region, first-wave, isolate, effective, likelihood, ENhance, assays, required, increase, changes in, contribute, the spike protein, increase in, regulated, suppressed, suppresse, suppress, airway epithelial cell, 【제목키워드】 innate immune,