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

Saichi, Melissa; Ladjemi, Maha Zohra; Korniotis, Sarantis; Rousseau, C.; Hamou, Zakaria Ait; Massenet-Regad, Lucile; Amblard, Elise; Noël, Floriane; Marie, Yannick; Bouteiller, Delphine; Medvedovic, Jasna; Pène, Frédéric; Soumelis, Vassili

doi:10.1038/s41556-021-00681-2

Cited by 126 publications

(117 citation statements)

References 76 publications

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“…Previous RNA-seq studies from COVID-19 patients have shown dysregulated immune profiles (36,37). A recent study by Combes et al showed a predominance of interferonstimulated genes (ISGincluding IFIT1-3) in all immune cells tested (neutrophils, macrophages, T and NK cells) from patients with mild COVID-19 (38).…”

Section: Discussionmentioning

confidence: 99%

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

et al. 2021

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COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells

et al. 2021

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“…The mechanisms behind the attenuated IFN response have been related with viral antagonism of STAT1 (Signal transducer and activator of transcription 1) phosphorylation [18] and significantly, life-threatening ARDS in COVID-19 patients have been associated with neutralizing auto-antibodies against IFN-I [ 19,20] and other inborn errors of IFN-I immunity [21]. Furthermore, single cell RNA sequencing of antigen-presenting cells revealed a lower expression of IFNAR1 and 2 in severe COVID-19 patients, suggesting a defect in IFN-α signaling, and also a downregulation of IFN-stimulated genes in both moderate and severe patients [22]. All these results support the essential role of IFN-I production in the first line of defense in COVID-19 for avoiding disease progression and point out to early immunotherapeutic strategies targeting this pathway.…”

Section: Discusionmentioning

confidence: 99%

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

et al. 2021

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Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFNα production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.

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“…Notably, plasmacytoid dendritic cells (PDCs), which are normally major producers of IFN-Is, are reduced in patients with severe COVID-19 and produce less IFN-α. However, PDCs isolated from healthy controls are efficiently activated by SARS-CoV2 in vitro and produce high levels of IFN-Is and -IIIs, suggesting that the PDC defects observed in COVID-19 reflect broader alterations in the host response rather than direct modulation by SARS-CoV-2 infection on PDC function ( Saichi et al., 2021 ). IFN-Is are potent antiviral factors, but they also promote the activation of DCs and induction of cytotoxic CD8+ T cells.…”

Section: Main Textmentioning

confidence: 99%