Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19
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Abstract
Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity–associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
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SciScore for 10.1101/2020.12.18.423363: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are several limitations to this work that should be noted. Though large for a multi-modal dataset, our sample size is still limited. Moreover, we were unable to profile each patient by all three single-cell modalities, preventing us from performing cross-modality validation on a perpatient basis. Additionally, our CyTOF panels …
SciScore for 10.1101/2020.12.18.423363: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are several limitations to this work that should be noted. Though large for a multi-modal dataset, our sample size is still limited. Moreover, we were unable to profile each patient by all three single-cell modalities, preventing us from performing cross-modality validation on a perpatient basis. Additionally, our CyTOF panels only allowed us to examine a limited number of cell types, preventing us from performing orthogonal validation of some transcriptional or epigenetic findings in proteomic space. This work profiled exclusively circulating immune cells; while understanding the peripheral immune system is critical to understanding aberrant and protective immune responses to SARS-CoV-2 infection, it does not capture the immune response at the site of infection. Finally, further functional experimentation is necessary to validate or refute many of the hypotheses presented here. Collectively, our work represents the first trimodal epigenomic, proteomic, and transcriptomic cell atlas of peripheral immune responses to COVID-19 across a broad spectrum of disease severity. By identifying novel immune features associated with COVID-19 mortality, as well as the immune status of patients with mild disease, our work enhances our understanding of pathological vs. protective immune responses and highlights several opportunities for therapeutic development.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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