A molecular single-cell lung atlas of lethal COVID-19

Melms, Johannes C.; Biermann, Jana; Huang, Huachao; Wang, Yiping; Nair, Ajay; Tagore, Somnath; Katsyv, Igor; Rendeiro, André F.; Amin, Amit Dipak; Schapiro, Denis; Frangieh, Chris J.; Luoma, Adrienne; Filliol, Aveline; Fang, Yinshan; Ravichandran, Hiranmayi; Clausi, Mariano Guardia; Alba, George A.; Rogava, Meri; Chen, Sean W.; Ho, Patricia; Montoro, Daniel T.; Kornberg, Adam; Han, Arnold; Bakhoum, Mathieu F.; Anandasabapathy, Niroshana; Suárez‐Fariñas, Mayte; Bakhoum, Samuel F.; Bram, Yaron; Borczuk, Alain C.; Guo, Xinzheng V.; Lefkowitch, Jay H.; Marboe, Charles C.; Lagana, Stephen M.; Portillo, Armando Del; Tsai, Emily J.; Zorn, Emmanuel; Markowitz, Glen S.; Schwabe, Robert F.; Schwartz, Robert E.; Elemento, Olivier; Saqi, Anjali; Hibshoosh, Hanina; Que, Jianwen; Izar, Benjamin

doi:10.1038/s41586-021-03569-1

Cited by 535 publications

(763 citation statements)

References 59 publications

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“…While many cells including epithelial, stromal, and immune cells likely contribute to the excessive release of inflammatory cytokines, monocytes, neutrophils, and macrophages are significant producers of tissue damaging cytokines. Monocytes and macrophages are also enriched in profibrotic genes consistent with fibroblast expansion (Melms et al, 2021), likely contributing to the lung fibrosis observed in severe COVID-19 patients. Several groups have also observed Together with a pathological inflammatory response, poor control of viral replication due to inadequate preexisting immunity, and delayed/inadequate type I interferon (IFN-I) responses likely contribute to the pathogenesis of severe COVID-19.…”

Section: A Pathological Inflammatory Response To Sars-cov-2 Infectionmentioning

confidence: 91%

An aberrant inflammatory response in severe COVID-19

Mérad

Subramanian

Wang

2021

Cell Host & Microbe

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Section: A Pathological Inflammatory Response To Sars-cov-2 Infectionmentioning

confidence: 91%

An aberrant inflammatory response in severe COVID-19

Mérad

Subramanian

Wang

2021

Cell Host & Microbe

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“…Similar to HIV-1, SARS-CoV-2 profoundly interacts and modifies the cellular physiology both on the transcriptional [169][170][171][172][173] and protein levels [128,170,174,175]. Host responses to SARS-CoV-2 vary substantially depending on viral load, infection stage, disease severity, body tissue, and cell type as well as age and sex of the host [172,176,177]. Coupled to the induction of an antiviral response, the expression of the SARS-CoV-2 receptor and interferon-responsive gene ACE2 is upregulated by the infected host cell in a viral load-dependent manner.…”

Section: Virus-host Interaction and Exploitation Of The Cellular Machinerymentioning

confidence: 99%

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Duerr¹,

Jimenez²,

Dittmann³

2021

Preprint

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SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped viruses with positive-stranded RNA and envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics delineating their distinct strategies for efficient spread.

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“…These studies have variously linked COVID-19 severity to CD8 T cells 16 , CD19 B cells 17 , eosinophils 18 , and myeloid cells 19 . Single-cell omic profiling has demonstrated the differential function of various immune cell types in severe disease as opposed to mild disease or non-infected condition [20][21][22][23][24][25] . However, these studies have focused on transcriptomics rather than the underlying genomics, and have been observational rather than predictive.…”

Section: Introductionmentioning

confidence: 99%

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity

Zhang

Cooper‐Knock

Weimer

et al. 2021

Preprint

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The determinants of severe COVID-19 in non-elderly adults are poorly understood, which limits opportunities for early intervention and treatment. Here we present novel machine learning frameworks for identifying common and rare disease-associated genetic variation, which outperform conventional approaches. By integrating single-cell multiomics profiling of human lungs to link genetic signals to cell-type-specific functions, we have discovered and validated over 1,000 risk genes underlying severe COVID-19 across 19 cell types. Identified risk genes are overexpressed in healthy lungs but relatively downregulated in severely diseased lungs. Genetic risk for severe COVID-19, within both common and rare variants, is particularly enriched in natural killer (NK) cells, which places these immune cells upstream in the pathogenesis of severe disease. Mendelian randomization indicates that failed NKG2D-mediated activation of NK cells leads to critical illness. Network analysis further links multiple pathways associated with NK cell activation, including type-I-interferon-mediated signalling, to severe COVID-19. Our rare variant model, PULSE, enables sensitive prediction of severe disease in non-elderly patients based on whole-exome sequencing; individualized predictions are accurate independent of age and sex, and are consistent across multiple populations and cohorts. Risk stratification based on exome sequencing has the potential to facilitate post-exposure prophylaxis in at-risk individuals, potentially based around augmentation of NK cell function. Overall, our study characterizes a comprehensive genetic landscape of COVID-19 severity and provides novel insights into the molecular mechanisms of severe disease, leading to new therapeutic targets and sensitive detection of at-risk individuals.

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A molecular single-cell lung atlas of lethal COVID-19

Cited by 535 publications

References 59 publications

An aberrant inflammatory response in severe COVID-19

An aberrant inflammatory response in severe COVID-19

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity

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