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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 |

REPOSITORIES: biostudies-literature

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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.

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

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