Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway

Daamen, Andrea R.; Bachali, Prathyusha; Owen, Katherine A.; Kingsmore, Kathryn M.; Hubbard, Erika L; Labonte, Adam C.; Robl, Robert; Shrotri, Sneha; Grammer, Amrie C.; Lipsky, Peter E.

doi:10.1038/s41598-021-86002-x

Cited by 130 publications

(140 citation statements)

References 79 publications

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“…The cutoff needed to establish which subjects will do worse, or need treatment, is being established in follow-up studies. Additionally, as we and others have previously reported, smaller differences in circulating proteins, especially in the context of complement activation, become apparent when studied locally (54,55). Reports on local complement deposition in autopsy specimens from patients with COVID-19 support this hypothesis (9, 10, 26).…”

Section: Discussionsupporting

confidence: 67%

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

et al. 2021

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Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., angiopoietin-2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

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Section: Discussionsupporting

confidence: 67%

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

et al. 2021

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“…Conversely, we have not observed significant downregulation of HLA-DR and other activation markers in antigen-presenting cells in COVID-19 patients compared with healthy adults. However, it should be noted that differences in gene expression may emerge according to the anatomical location of cells (46) and disease severity. Indeed, reduced HLA-DR expression appears to be more pronounced in patients with severe COVID-19 infection (16,18,(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients

et al. 2021

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Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.

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“…To understand the expression pattern of host genes upon SARS-CoV-2 infection, we analysed the RNA sequencing dataset (accession number is GSE147507 - Illumina NextSeq 500 Platform) [ 18 , 19 ] generated from the SARS-CoV-2 infected lung tissues [ https://www.ncbi.nlm.nih.gov/geo/ ]. The full details of experimental protocol including the samples, RNA extraction and sequence analysis are provided in the original publication [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Multilevel systems biology analysis of lung transcriptomics data identifies key miRNAs and potential miRNA target genes for SARS-CoV-2 infection

Banaganapalli

Alrayes²,

Awan

et al. 2021

Computers in Biology and Medicine

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Background The spread of a novel severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has affected both the public health and the global economy. The current study was aimed at analysing the genetic sequence of this highly contagious corona virus from an evolutionary perspective, comparing the genetic variation features of different geographic strains, and identifying the key miRNAs as well as their gene targets from the transcriptome data of viral infected lung tissues. Methods A multilevel robust computational analysis was undertaken for viral genetic sequence alignment, phylogram construction, genome-wide transcriptome data interpretation of virus-infected lung tissues, miRNA mapping, and functional biology networking. Results Our findings show both genetic similarities as well as notable differences in the S protein length among SARS-CoV-1, SARS-CoV-2 and MERS viruses. All SARS-CoV-2 strains showed a high genetic similarity with the parent Wuhan strain, but Saudi Arabian, South African, USA, Russia and New Zealand strains carry 3 additional genetic variations like P333L (RNA -dependant RNA polymerase), D614G (spike), and P4715L (ORF1ab). The infected lung tissues demonstrated the upregulation of 282 (56.51%) antiviral defensive response pathway genes and downregulation of 217 (43.48%) genes involved in autophagy and lung repair pathways. By miRNA mapping, 4 key miRNAs ( hsa-miR-342-5p, hsa-miR-432-5p, hsa-miR-98-5p and hsa-miR-17-5p ), targeting multiple host genes ( MYC, IL6, ICAM1 and VEGFA ) as well as SARS-CoV2 gene ( ORF1ab ) were identified. Conclusion Systems biology methods offer a new perspective in understanding the molecular reasons underlying the faster spread of SARS-CoV-2 infection. The antiviral miRNAs identified in this study may aid in the ongoing search for novel personalized therapeutic avenues for COVID patients.

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Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway

Cited by 130 publications

References 79 publications

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients

Multilevel systems biology analysis of lung transcriptomics data identifies key miRNAs and potential miRNA target genes for SARS-CoV-2 infection

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