Boucau, J. | bioRxiv Science

bioRxiv2022

Anamnestic Humoral Correlates of Immunity Across SARS-CoV-2 Variants of Concern

While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across VoCs, including the Delta and more distant Omicron variant of concern (VoC), remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals recently infected with either the Delta or Omicron VoC. While limited acute N-terminal domain and RBD-specific immune expansion was observed following breakthrough, a significant immunodominant expansion of opsinophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed 1 week after breakthrough infection. This S2-specific functional humoral response continued to evolve over 2-3 weeks following both Delta and Omicron breakthrough infection, targeting multiple VoCs and common coronaviruses. These responses were focused largely on the fusion peptide 2 and heptad repeat 1, both associated with enhanced rates of viral clearance. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the control of SARS-CoV-2 infection, across VOCs, and thus humoral response linked to virus attenuation can guide next-generation generation vaccine boosting approaches to confer broad protection against future SARS-CoV-2 VoCs.

immunology↗

bioRxiv2022

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

microbiology↗