Fig. 5.

Molecular mechanisms underlying the milder disease phenotype in Δ382 SARS-CoV-2 infections. A SARS-CoV-2 variant with a 382-nucleotide deletion (Δ382) truncates ORF7b and removes the ORF8 transcription-regulatory sequence, eliminating ORF8 transcription. The ORF8 382-nt deletion has recently been associated with a milder disease phenotype. The attenuation of SARS-CoV-2 ORF8 upregulates eIF2 signaling and cellular stress responses at the acute phase of infection, potentially interrupting the downregulation of MHC-I molecules by ORF8 and also enhances the activation of both CD4⁺ and CD8⁺ T cells, evidenced by enrichment of effector cytotoxic genes and upregulation of SARS-CoV-2 specific T cell responses in Δ382 SARS-CoV-2 infected patients. Enhanced T cell responses may in turn mediate rapid and effective antibody responses in Δ382 SARS-CoV-2 infection. More pronounced cellular stress responses may further reduce systemic inflammation and dysfunctional neutrophils in Δ382 SARS-CoV-2 infected patients. Overall, the attenuation of SARS-CoV-2 ORF8 produced a molecular phenotype characterized by more pronounced cellular stress responses and a less dysregulated immune phenotype with more robust T and B cell responses. ORF, open reading frame; eIF2, eukaryotic initiation factor 2; MHC-I, major histocompatibility complex 1; CD, cluster of differentiation