Dataset Information

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

ABSTRACT: A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanisms, we examined publicly available RNA-Sequencing data using CIBERSORTx and conducted a Ingenuity Pathway Analysis to address this knowledge gap. In complement to these findings, we used bioinformatics tools to analyze publicly available RNA sequencing data and found that upregulation of complement may be leading to a downregulation of T-cell activity in lungs of severe COVID-19 patients. Thus, targeting treatments aimed at the modulation of classical complement and T-cell activity may help alleviate the proinflammatory effects of COVID-19, reduce lung pathology, and increase the survival of COVID-19 patients.

SUBMITTER: Howell MC

PROVIDER: S-EPMC8652259 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

Howell Mark C MC Green Ryan R McGill Andrew R AR Kahlil Roukiah M RM Dutta Rinku R Mohapatra Shyam S SS Mohapatra Subhra S

Frontiers in immunology 20211124

A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanism ...[more]

PMID: 34899680

Similar Datasets

Project description:For the purpose of establishing a mice model for sever COVID-19 , mice were infected intranasally with SARS-CoV-2 two days after pulmonary application of low-dose ricin. The goal of this study is to perform a comparative transcriptomic analysis by exploring the alterations in gene expression in lungs of mice exposed to low-dose ricin and SARS-CoV-2 (samples OR009-OR012) compared to lungs of mice infected solely with SARS-CoV-2 (48 hr after infection, samples OR021-OR024) or mice exposed to low-dose ricin (96 hr post exposure,samples OR005-OR008)) or mice exposed to lethal dose of ricin (48 hr post exposure, samples OR013-OR016). Methods: Total RNA was extracted from lungs of ricin intoxicated mice (intranasally exposure to 1.7 µg/kg or 10 µg/kg ricin ) or of SARS-CoV-2 infected mice (intranasal administration of 5 x 106 PFU), using the RNeasy mini kit (Qiagen). RNA-seq libraries were constructed and sequencing of 100bp paired-end was performed on the Illumina NovaSeq 6000 system. Sequencing yielded about 22M reads per sample that were mapped to the mouse genome. RNA ratios were clustered using partitioning clustering. We next carried out Ingenuity Pathway Analysis (IPA). Results: Principal component analysis revealed distinct transcriptional signatures between lungs mice exposed to low-dose ricin and infected with SARS-CoV-2 compared to lungs of mice infected solely with SARS-CoV-2 or mice exposed to low-dose ricin (96 hr post exposure) or mice exposed to lethal dose of ricin (48 hr post exposure). Differentially Expressed Genes (DEGs) were defined as such when having false discovery rate (FDR) value (p-adjusted) of ≤ 0.01 and a fold change (FC) of ≥ 1.5 or ≤ 0.66. Analysis of Low-dose-ricin-treated mice transcripts resulted in the detection of 6684 DEGs, 55% upregulated and 45% downregulated. Similarly, in Low-dose-ricin-treated mice infected with SARS-CoV-2, we found a total of 6044 differentially expressed genes, 52% induced and 48% repressed. Considerably fewer (797, 67% upregulated and 33% downregulated) differentially expressed genes were identified in lungs of mice infected only with SARS-CoV-2.

Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF; CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.

Dataset Information

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

Publications

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets