Deciphering the state of immune silence in fatal COVID-19 patients

Abstract

Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocytosis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely impeding the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune signature of disease severity that correlated with the accumulation of naive lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found monocyte and neutrophil immune suppression loss associated with fatal clinical outcome in severe pa-tients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allel, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of myeloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to immune silence in patients facing death.

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

“…We find evidence that ERG is central to a gene network linked to these cell populations, encoding a transcription factor important in determining lineage plasticity, modulating inflammation and maintaining an antithrombotic environment (Yuan et al, 2009). We further identify hallmarks supporting the importance of mononuclear phagocyte dysfunction in severe disease (Bost et al, 2021;Schulte-Schrepping et al, 2020), namely proliferating cMono, and specific monocyte populations showing reduced HLA-DR, CD33 and CD11c expression, high expression of antioxidant metallothionein and S100A8/9/12 (calprotectin), together with reduced pDCs.…”

“…A dysregulated hyperinflammatory state occurs in some individuals (Moore and June, 2020), consistent with reported benefits from glucocorticoids (dexamethasone) and inhibitors of the IL-6 receptor (tocilizumab/sarilumab) and Janus kinases (baricitinib) in severe disease (Gordon et al, 2021;Horby et al, 2021a;Horby et al, 2021b;Kalil et al, 2021). Nevertheless, blood-derived signatures of COVID-19 severity are diverse, including evidence of immune suppression, myeloid dysfunction, lymphopenia, interferon driven immunopathology, T cell activation as well as exhaustion, and immune senescence (Bost et al, 2021;Chen and Wherry, 2020;Diao et al, 2020;Hadjadj et al, 2020;Mann et al, 2020;Schulte-Schrepping et al, 2020). In the lung, widespread neutrophil and macrophage infiltration, T cell cytokine production and alveolitis are seen with features of altered redox balance, endothelial damage and thrombosis (Grant et al, 2021).…”

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

“…6A). This population has been identified in other COVID-19 datasets but is not yet well-characterized (21,63). These cells specifically and highly expressed genes encoding markers expressed at distinct stages in neutrophil development, including DEFA1B, LCN2, and MMP8 (Fig.…”

“…4J and suggests that the activated phenotype observed in these samples may be driven by activating signals received through DNAM-1 and NKG2D as well as a lack of inhibitory signaling through CD161. A hyperactivated neutrophil signature marks severe and fatal COVID-19 Despite evidence that neutrophils are major players in the dysregulated immune response defining severe and fatal COVID-19 (16,(18)(19)(20)(63)(64)(65)(66), there is a relative dearth of deep profiling of neutrophils from COVID-19 patients given their sensitivity to both cryopreservation and mechanical stimulation (67,68). To address this, we demonstrated that Seq-Well generated high-quality scRNA-seq data of primary human neutrophils from a healthy blood donor (Fig.…”

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

“…These results are similar to the previous reports describing the accumulation of MDSCs in patients with sepsis and septic shock [136][137][138] . In a recent preprint study, scRNA-seq was used to profile immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of patients with COVID-19 and healthy controls 139 . This analysis revealed an immune signature of the disease severity that correlated with the accumulation of naive lymphoid cells in the lung and the expansion and activation of myeloid cells in peripheral blood.…”