Single-cell analysis reveals cell communication triggered by macrophages associated with the reduction and exhaustion of CD8+ T cells in COVID-19

Abstract

Background The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand–receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. Methods A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand–receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1β, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. Results Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand–receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. Conclusions Our study showed that macrophages driving ligand–receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1β, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. Trial registration: This is a retrospective observational study without a trial registration number.

Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium

“…Our IPA analysis showed that activation of cytokines IL6, IL16, CXCL1, CXCL3, CXCL5, CXCL6, CXCL8, CXCL10, and CCL20 are a hallmark signature of cytokine response in COVID-19 patients [ 21 , 22 ]. Our finding is aligned with several reports from recent studies on SARS-CoV-2 induced transcriptomic landscape [ 23 – 25 ]. We also found increased levels of key pro-apoptotic factors like BCL2A1, LTF, SOX6, SPP1, and SYNE1.…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Other critical hub-high traffic genes in the blue module included EP300 ( 146 , 147 ), CDK1 ( 4 , 148 ), VEGFA ( 149 – 151 ), CTNNB1 ( 151 , 152 ), IL10 ( 9 , 153 – 155 ), SOCS1 , SOCS3 ( 156 ), SIRT1 ( 157 , 158 ), TFRC ( 159 – 161 ), HSP90AB1 ( 162 ), CYCS ( 163 ), EZR ( 164 ), TNFAIP3 , ICAM1 ( 10 ), and PIK3R1 ( 139 ) as well as TFs such as ATF4 ( 165 ), ATF3 ( 166 , 167 ), and BCL6 ( 152 ) which have important roles in pathogenesis of SARS-CoV-2, and some of which are potential therapeutic targets. For instance, SOCS1 / 3 antagonists may be prophylactic or therapeutic against the COVID-19 pandemic ( 156 ).…”

Rapid Manufacturing of Highly Cytotoxic Clinical-Grade SARS-CoV-2-specific T Cell Products Covering SARS-CoV-2 and Its Variants for Adoptive T Cell Therapy

“…The repertoire of SARS-CoV-2-specific T cells in COVID-19 patients convalescent from mild disease covers a broad range of viral antigens including antigens from different VOCs. In contrast, in the majority of hospitalized patients reduced functionally active antiviral T cells are observed ( Bergamaschi et al, 2021 ; Bonifacius et al, 2021 ; He et al, 2021 ). Adoptive transfer of virus-specific T cells in different settings appears safe and effective ( Withers et al, 2017 ).…”

“…On the other hand, some patients do not mount an appropriate, efficient T cell reaction but exhibit inadequate immune responses ( Jarjour et al, 2021 ). Patients with severe COVID-19 generally develop lymphopenia, disruption of the T cell compartment, and CD8 + memory T cell exhaustion ( Bacher et al, 2020 ; He et al, 2021 ; Vigón et al, 2021 ). Reduced T cell counts and an increased granulocyte to lymphocyte ratio correlate with disease severity and are early predictive markers of an adverse course ( Kong et al, 2020 ; Liu et al, 2020 ).…”