Immunological and metabolic characteristics of the Omicron variants infection

Abstract

The Omicron variants of SARS-CoV-2, primarily authenticated in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wildtype SARS-CoV-2. Omicron could hardly be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescents infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8 + T cell epitopes, compared with Delta. These epitopes could induce robust CD8 + T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8 + T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted the response of memory T cells. Consistently, a greater fraction of memory CD8 + T cells existed in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.

Fig. 1

Immune escape by the BA.1 Omicron variant. a The ELISA assay shows the binding ability of 3A2A12, MM43, MM48 and mouse IgG to SARS-CoV-2 RBD (n = 4). b The neutralizing ability of 3A2A12 for SARS-CoV-2 and BA.1 Omicron pseudoviruses (n = 3), p < 0.001, determined by two-way ANOVA. c Inhibition of Delta and BA.1 Omicron pseudoviruses by convalescent patient sera (n = 10). d Inhibition of Delta (left) and BA.1 Omicron (right) pseudoviruses by COVID-19 convalescent patient sera in vaccinees (n = 6) and non-vaccinated group (n = 4). Data are represented as mean ± SEM, p-value was determined by the Wilcoxon rank sum test, (*p < 0.05, **p < 0.01, ***p < 0.001)

Fig. 2

Immune response of Omicron to Delta-specific CD8 + T cells. a (Top) The percentage of TNF-α + cells in total CD8 + T cells in vaccinated convalescent individuals (n = 6) and convalescent individuals without vaccination (n = 4). (Bottom) The absolute number of TNF-α + cells in vaccinated convalescent individuals (n = 6) and convalescent individuals without vaccination (n = 4). b (Top) The percentage of TNF-α + cells in total CD8 + T cells in 2-doses vaccinees (n = 12) and 3-doses vaccinees (n = 7). (Bottom) The absolute number of TNF-α + cells in total CD8 + T cells in 2-doses vaccinees (n = 12) and 3-doses vaccinees (n = 7). Data are represented as mean ± SEM, p-value was determined by the wilcoxon rank sum test

Fig. 3

Metabolic profiling of SARS-CoV-2, Delta or Omicron-specific CD8 + T cells from 3-dose vaccinees. a The differential metabolic profiling of Delta vs SARS-CoV-2. b The differential metabolic profiling of BA.1 Omicron vs SARS-CoV-2. c KEGG analysis of difference metabolites of SARS-CoV-2 vs Delta, and SARS-CoV-2 vs Omicron, from 3-dose vaccinees. Data are represented as mean ± SEM

Fig. 4

Difference in T cell differentiation after stimulated by SARS-CoV-2 variants. a–c Fraction of effector T cells (TE) (a), Treg cells (b), and effector memory T cells (TEM) (c) among SARS-CoV-2, Delta or Omicron-specific CD8 + T cells, respectively. d Fraction of TEMs in Omicron-specific CD8 + T cells before and after G6PDi-1 treatment. Data are represented as mean ± SEM, p-value was determined by two-way ANOVA

Fig. 5

Human CD147 transgenic mouse model with BA.1 Omicron infection exhibited exudative alveolar inflammation. Inoculation mice via the intranasal at 3 × 10⁵ TCID₅₀ of BA.1 Omicron, and sample collected at 3 and 6 d.p.i. a RT-qPCR for viral RNA levels in the lung, nose, throat, trachea, and bronchus (n = 4). b Virions in the alveolar type II cells, neutrophils and macrophages in lung tissues of human CD147 transgenic mice (at 3 d.p.i.) were detected by electron microscopy (scale bars, 500 nm). c H&E staining of tissues sections from infected human CD147 transgenic mice (scale bars, 200 μm). d Gene expression of cytokines and chemokines in lung homogenates determined by RT-qPCR (n = 4). Data are represented as mean ± SEM, p-values were determined by two-tailed student t-test, **p < 0.01, ***p < 0.001

Fig. 6

CD147 is a target for the treatment of COVID-19 caused by Omicron. Human CD147 transgenic mice were intranasally inoculated with 3 × 10⁵ TCID₅₀ Omicron and treated with meplazumab the next day. a RT-qPCR for viral RNA levels in lung tissues at 3 and 6 d.p.i. (n = 4). b H&E staining of lung tissue sections from the IgG and meplazumab groups at 3 and 6 d.p.i. (scale bars, 200 μm). c Gene expression of cytokines and chemokines in lung homogenates determined by RT-qPCR, compared with the corresponding IgG controls at 3 d.p.i. (top) and 6 d.p.i. (bottom) (n = 4). Gapdh was used as a reference gene. Data are represented as mean ± SEM, p-values were determined by two-tailed student t-test, *p < 0.05, **p < 0.01, ***p < 0.001