COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis

Chua, Robert Lorenz; Lukassen, Soeren; Trump, Saskia; Hennig, Bianca P.; Wendisch, Daniel; Pott, Fabian; Debnath, Olivia; Thürmann, Loreen; Kurth, Florian; Völker, Maria Theresa; Kazmierski, Julia; Timmermann, Bernd; Twardziok, Sven; Schneider, Stefan; Machleidt, Felix; Müller-Redetzky, Holger; Maier, Melanie; Krannich, Alexander; Schmidt, Sein; Balzer, Felix; Liebig, Johannes; Loske, Jennifer; Suttorp, Norbert; Eils, Jürgen; Ishaque, Naveed; Liebert, Uwe G.; Kalle, Christof von; Hocke, Andreas C.; Witzenrath, Martin; Goffinet, Christine; Drosten, Christian; Laudi, Sven; Lehmann, Irina; Conrad, Christian; Sander, Leif Erik; Eils, Roland

doi:10.1038/s41587-020-0602-4

Cited by 1,007 publications

(1,323 citation statements)

References 64 publications

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“…These findings implied that the induction of ACE2 expression in IFN-high conditions could result in an amplified risk of SARS-CoV-2 infection 4,5 . Concerns could also be raised about possible ACE2-inducing side effects of IFN-based treatments proposed for COVID-19 [6][7][8][9] .…”

Section: Introductionmentioning

confidence: 91%

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Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

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Section: Introductionmentioning

confidence: 91%

“…Furthermore, ACE2 was proposed to be an ISG, based on its inducible expression in cells treated with interferons (IFNs) or infected by viruses that induce IFN responses, such as influenza 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…C-C chemokine receptor type 5 (CCR5) plays a central role in modulating immune cell trafficking to sites of inflammation, inhibition of which may suppress the hyperactive immune response observed in COVID-19 patients. 58 Leronlimab, a CCR5 antagonist, is being evaluated in patients who experience respiratory illness as a result of COVID-19 at a single dose of 700 mg intravenously, consistent with the dose used in the ongoing breast cancer trial. CD147, a receptor on host cells, is considered a novel route for SARS-CoV-2 invasion, and it is hypothesized that there exists an inhibitory potential for drugs interfering with CD147 on SARS-CoV-2 invasion.…”

Section: Other Immunomodulatory Therapiesmentioning

confidence: 99%

Immunomodulatory Therapeutic Proteins in COVID‐19: Current Clinical Development and Clinical Pharmacology Considerations

Chen

Golding

et al. 2020

The Journal of Clinical Pharma

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The coronavirus disease 2019 (COVID‐19) pandemic caused by infection with SARS‐CoV‐2 has led to more than 600 000 deaths worldwide. Patients with severe disease often experience acute respiratory distress characterized by upregulation of multiple cytokines. Immunomodulatory biological therapies are being evaluated in clinical trials for the management of the systemic inflammatory response and pulmonary complications in patients with advanced stages of COVID‐19. In this review, we summarize the clinical pharmacology considerations in the development of immunomodulatory therapeutic proteins for mitigating the heightened inflammatory response identified in COVID‐19.

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“…Severe COVID-19 patients display some shared features of sepsis, including secretion of in ammatory cytokines, neutrophil hyper-activation, reduced function of natural killer (NK) and dendritic cells (DC), altered monocyte activation and lymphopenia [7,17]. Several high dimensional phenotypic and molecular approaches were deployed in order to dissect the biology of virus-immune system interaction during COVID-19 pathogenesis [7,16,[18][19][20][21][22]. These analyses were performed on peripheral blood and peripheral blood mononuclear cells (PBMCs) isolated from patients with different disease severity.…”

Section: Introductionmentioning

confidence: 99%

“…A speci c genetic locus including immune related genes (such as C-X-C motif chemokine receptor 6 -CXCR6), was found to be associated with worse prognosis in COVID-19 patients [23]. Other studies exclusively performed on broncho-alveolar lavage uids (BAL), elucidated the sustained interplay between macrophages releasing in ammatory cytokines and lung epithelial cells in more severe COVID-19 disease stages [21], whereas pointed out highly clonally expanded CD8 + T cells in moderate patients [22]. Here we de ne a complete atlas of COVID-19 patients' immune landscape integrating both local (lung) and systemic (blood) tissues, harmonizing molecular (single cell RNA sequencing, scRNA-seq), functional and clinical data, in order to dissect the complex interplay established by SARS-CoV-2 with host immune system.…”

Section: Introductionmentioning

confidence: 99%

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

Amit

Bost

Sanctis

et al. 2020

Preprint

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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 lymphohistiocyto-sis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely imped-ing 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 sig-nature of disease severity that correlated with the accumulation of naïve 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 mon-ocyte 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.

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COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis

Cited by 1,007 publications

References 64 publications

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Immunomodulatory Therapeutic Proteins in COVID‐19: Current Clinical Development and Clinical Pharmacology Considerations

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

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