Dataset Information

Quantitative proteomics analysis of COVID-19 infected hamster lung tissue

ABSTRACT: The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1 and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant marginal reduction in mitochondrial respiration was also observed as seen by a partial loss of oxygen consumption rates (OCR) in both coupled and uncoupled states of respiration in isolated mitochondrial fractions of SARS-CoV-2 infected hamster lungs. Proteomics analysis revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1 in inflammatory macrophages may also drive proinflammatory cytokines production, complement activation, and oxidative stress in infected lungs. Together, these findings support a role for HIF-1 as a central mediator of the metabolic reprogramming, inflammation, and mitochondrial dysfunction associated with COVID-19 disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mesocricetus Auratus (golden Hamster)

TISSUE(S): Lung

SUBMITTER: Michael Heaven

LAB HEAD: Abdu Alayash

PROVIDER: PXD036862 | Pride | 2023-03-10

REPOSITORIES: Pride

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Publications

HIF-1α-Dependent Metabolic Reprogramming, Oxidative Stress, and Bioenergetic Dysfunction in SARS-CoV-2-Infected Hamsters.

Jana Sirsendu S Heaven Michael R MR Stauft Charles B CB Wang Tony T TT Williams Matthew C MC D'Agnillo Felice F Alayash Abdu I AI

International journal of molecular sciences 20221229 1

The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1α and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glu ...[more]

PMID: 36614003

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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.

			Action	DRS
	HamsterC1_20211014175232.raw	Raw
	HamsterC1_20211014175232.rawseq.csv	Csv
	HamsterC2.raw	Raw
	HamsterC2.rawseq.csv	Csv
	HamsterC3.raw	Raw