Single cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Abstract

COVID-19 can lead to life-threatening acute respiratory failure, characterized by simultaneous increase in inflammatory mediators and viral load. The underlying cellular and molecular mechanisms remain unclear. We performed single-cell RNA-sequencing to establish an exhaustive high-resolution map of blood antigen-presenting cells (APC) in 7 COVID-19 patients with moderate or severe pneumonia, at day-1 and day-4 post-admission, and two healthy donors. We generated a unique dataset of 31,513 high quality APC, including monocytes and rare dendritic cell (DC) subsets. We uncovered multiprocess and previously unrecognized defects in anti-viral immune defense in specific APC compartments from severe patients: i) increase of pro-apoptotic genes exclusively in pDC, which are key effectors of antiviral immunity, ii) sharp decrease of innate sensing receptors, TLR7 and DHX9, in pDC and cDC1, respectively, iii) down-regulation of antiviral effector molecules, including Interferon stimulated genes (ISG) in all monocyte subsets, and iv) decrease of MHC class II-related genes, and MHC class II transactivator (CIITA) activity in cDC2, suggesting a viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore defective immune defense.

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

“…Interestingly, then, in a cohort of asymptomatic SARS-CoV-2-infected individuals circulating pDC were already reduced in the peripheral blood as respect to the healthy counterpart but significantly higher than what found in hospitalized COVID-19 patients. In accordance with these data, a recent paper performed a single-cell RNA sequencing of PBMC from moderate or severe COVID-19 and highlighted increased pro-apoptotic pathways in pDC of severely infected patients pointing towards a mechanism that may explain insufficient control of SARS-CoV-2 infection [ 61 ]. Nonetheless, we also found that the phenotype was drastically different in pDC derived from severely infected or asymptomatic subjects.…”

Circulating Type I Interferon Levels and COVID-19 Severity: A Systematic Review and Meta-Analysis

“…Further studies addressed the role of IFN-I during SARS-CoV-2 infection, analyzing IFN-I and ISGs gene expression using molecular approaches, particularly single-cell RNA sequencing analysis, which was also not included in our metaanalysis (86)(87)(88). Studies carried out with single-cell RNA sequencing determined a hyperactivation of the IFN-I signaling pathways in critically ill patients, contributing to immune dysfunction, leading to exaggerated reactions that can damage tissues and impair the patient's evolution (88,89) mainly at the pulmonary level.…”

A bird's eye view on the role of dendritic cells in SARS‐CoV‐2 infection: Perspectives for immune‐based vaccines

“…These mechanisms uncovered previously unknown defects related to both innate and adaptive immunity in SARS‐Cov‐2 infection. 80 In this regard, it has been demonstrated that low frequencies of CD8 + T lymphocytes predict high mortality and clinical severity of COVID‐19 pneumonia. 81 , 82 In analogy with these findings, it may be hypothesized that any progressive immune‐associated injury and inadequacy could have detrimental effects on acute COVID‐19 outcomes.…”