Project description:The clinical presentations and outcomes of SARS-CoV-2 infection are highly variable, ranging from asymptomatic infections to severe conditions, and the underlying mechanisms remain largely unknown. In this study, we performed the single-cell RNA sequencing to examine the profiles of the peripheral blood mononuclear cells (PBMCs) from the healthy controls (HC), asymptomatic individuals (AS) and symptomatic COVID-19 patients (SM) with various clinical features and disease severity. We first identified nine major cell types, including T cells, B cells, monocytes, natural killer (NK) cells, dendritic cells (DC), platelets, neutrophils, plasma cells and stem cells from a total of 119,799 single cells captured and filtered for the final analysis, and then divided these cell types into separate cell clusters and sub-clusters, respectively. We revealed that SARS-CoV-2 infection resulted in profound alternations in various cellular compartments and identified a number of distinct immune cell subsets that were associated with various clinical presentations, disease severity and viral persistence of COVID-19. (NCAM1+CD160+) NK cells increased significantly in AS and SM individuals compared with the HC. SM patients showed a significant increase in (LAG3+CD160+CD8+) NKT cells and a decrease in (CD4-CD8-) double negative T cells compared with the AS subjects. (CD68-CSF1R-IL1BhiCD14+) classical monocytes were significantly higher in patients with severe disease (SD) than the patients with moderate disease (MD). (CD68-CSF1R-IL1BhiCD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were positively and negatively correlated with the age-related disease severity of COVID-19 patients, respectively. Increases in (CD33-HLA-DMA-CD14+) classical monocytes and (CLEC10A-S100A9lo)pDC were associated with long-term nucleic acid test positive (LTNP) patients compared with the short-term nucleic acid test positive (STNP) individuals. Increases in (LAG3+CD160+CD8+) NKTcells and (FOXP3+IL2RA+IL7R+CD4+) Treg cells were observed in a patient lacking B cells and plasma cells. Dramatic increases in neutrophils, (CD33-HLA-DMA-CD14+) classical monocytes, and (CD68-CSF1R-IL1BhiCD14+) classical monocytes were detected at a later stage of a fatal patient. Our findings may enhance our understanding of the immune cell alternations involved in the pathogenesis of COVID-19 and the protective immune responses against SARS-CoV-2 infection.

Project description:Despite their remarkable success, the effectiveness of COVID-19 mRNA vaccines is notably diminished in organ transplant patients. Here, we employed a multi-omics approach to elucidate the immunological state at baseline and following SARS-CoV-2 mRNA vaccination of lung transplant (LTX) patients compared to healthy controls (HC). Our analysis revealed a baseline immune profile in LTX patients that mirrors the immune alterations observed in severe COVID-19 cases and sepsis. This profile is characterized by: (i) elevated pro-inflammatory cytokines in plasma, notably high levels of EN-RAGE and IL-6; (ii) reduced expression of HLA-DR on blood monocytes and dendritic cells (DCs); (iii) diminished cytokine production by blood monocytes and DCs in response to toll-like receptor (TLR) activation; (iv) increased plasma concentrations of microbial products. In addition to these alterations, single-cell RNA-seq analysis revealed 4 transcriptionally distinct clusters of classical monocytes in HC, with a striking enrichment of a unique classical monocyte cluster in LTX patients, differing from the predominant classical monocytes in HC, marked by heightened expression of the S100A family and reduced expression of genes related to cytokine production and antigen presentation. Following vaccination, LTX patients displayed a reduced magnitude and breadth of binding and neutralizing antibody responses, and impaired memory B and T cell responses. Furthermore, there was a blunted innate immune response to vaccination, evidenced by decreased transcriptional signatures linked to antigen presentation, dendritic cell activation, interferon and monocytes at the single-cell level. Integrative multiscale, multiresponse network (MMRN) analysis revealed an inverse correlation between the distinctive baseline immunological state observed in LTX patients and the adaptive immune responses to vaccines. These findings underscore the distinct immunological profile of lung transplant recipients, providing insights into their immunosuppressed condition and reduced immune responses to vaccines.

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Transcriptomes of classical monocytes in post-COVID patients suggest predisposing condition or innate memory from SARS-CoV-2 infection

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