Multi-omics evaluation of SARS-CoV-2 infected mouse lungs reveals dynamics of host responses

Wang, Zhao Ni; Yang, Xiang; Sun, Jing; Zhao, Jin; Zhong, Nan; Tang, Xiao Xiao

doi:10.1016/j.isci.2022.103967

Cited by 7 publications

(15 citation statements)

References 91 publications

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“…Cell lines have homogenous populations that exhibit aberrant kinase activity and may not recapitulate certain infection dynamics that would be seen in diverse cell populations seen in primary lung tissues. Recent work evaluating the kinase response to SARS-CoV-2-infected mice, rhesus macaques, and humans has highlighted similar dysregulated pathways as those in our study. ,, However, it is unclear if signaling by shared pathways is coordinately regulated following infection since there are differing results depending on the model platform. For example, in the mouse and rhesus macaque lung model, there is upregulation of the PI3K/AKT/mTOR, p38, and MAPK signaling pathways; however, the AKT pathway is downregulated in nasopharyngeal swabs collected from SARS-CoV-2 patients. ,, One aspect of the dysregulation in these models is that it may be temporal and compartment specific; thus, it is difficult to compare to our cellular data due to the large cytopathic effect seen by 24 hpi in vitro .…”

Section: Discussionsupporting

confidence: 65%

Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals

Fritch,

Mordant,

Gilbert

et al. 2023

J. Proteome Res.

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Host kinases play essential roles in the host cell cycle, innate immune signaling, the stress response to viral infection, and inflammation. Previous work has demonstrated that coronaviruses specifically target kinase cascades to subvert host cell responses to infection and rely upon host kinase activity to phosphorylate viral proteins to enhance replication. Given the number of kinase inhibitors that are already FDA approved to treat cancers, fibrosis, and other human disease, they represent an attractive class of compounds to repurpose for host-targeted therapies against emerging coronavirus infections. To further understand the host kinome response to betacoronavirus infection, we employed multiplex inhibitory bead mass spectrometry (MIB-MS) following MERS-CoV and SARS-CoV-2 infection of human lung epithelial cell lines. Our MIB-MS analyses revealed activation of mTOR and MAPK signaling following MERS-CoV and SARS-CoV-2 infection, respectively. SARS-CoV-2 host kinome responses were further characterized using paired phosphoproteomics, which identified activation of MAPK, PI3K, and mTOR signaling. Through chemogenomic screening, we found that clinically relevant PI3K/mTOR inhibitors were able to inhibit coronavirus replication at nanomolar concentrations similar to direct-acting antivirals. This study lays the groundwork for identifying broad-acting, hosttargeted therapies to reduce betacoronavirus replication that can be rapidly repurposed during future outbreaks and epidemics. The proteomics, phosphoproteomics, and MIB-MS datasets generated in this study are available in the Proteomics Identification Database (PRIDE) repository under project identifiers PXD040897 and PXD040901.

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Section: Discussionsupporting

confidence: 65%

Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals

Fritch,

Mordant,

Gilbert

et al. 2023

J. Proteome Res.

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“…In agreement with our hypothesis, a recent multi-omics study revealed that many kinases of the CDK family mediated signal transduction during SARS infection by interacting with each other and served as functional hubs. 24 More importantly, several specific CDK inhibitors are effective in treating cancer. 25 These CDK inhibitors could be repurposed as effective therapeutics to treat SARS-CoV-2 infections.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis

Guo

Lei

Chang

et al. 2022

Sig Transduct Target Ther

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The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.

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“…The role of the cell cycle in the development of COVID-19 heart injury was documented in a gene set enrichment (GSE) analysis of human-induced pluripotent stem-cells-derived cardiomyocytes infected with SARS-CoV-2, which revealed a substantial reduction in the expression of genes related to G2/M checkpoint [ 90 ]. Alterations of the cell-cycle progress were also documented in lung tissues in a mouse model, where a multi-omics study showed dynamic changes in cell cycles in conjunction with alterations in the CDK and MAPK signaling networks [ 91 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Network Analysis of the Transcriptome Impact of SARS-CoV-2 Interacting MicroRNAs in COVID-19 Disease

Moatăr

Chis

Marian

et al. 2022

IJMS

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According to the World Health Organization (WHO), as of June 2022, over 536 million confirmed COVID-19 disease cases and over 6.3 million deaths had been globally reported. COVID-19 is a multiorgan disease involving multiple intricated pathological mechanisms translated into clinical, biochemical, and molecular changes, including microRNAs. MicroRNAs are essential post-transcriptional regulators of gene expression, being involved in the modulation of most biological processes. In this study, we characterized the biological impact of SARS-CoV-2 interacting microRNAs differentially expressed in COVID-19 disease by analyzing their impact on five distinct tissue transcriptomes. To this end, we identified the microRNAs’ predicted targets within the list of differentially expressed genes (DEGs) in tissues affected by high loads of SARS-CoV-2 virus. Next, we submitted the tissue-specific lists of the predicted microRNA-targeted DEGs to gene network functional enrichment analysis. Our data show that the upregulated microRNAs control processes such as mitochondrial respiration and cytokine and cell surface receptor signaling pathways in the heart, lymph node, and kidneys. In contrast, downregulated microRNAs are primarily involved in processes related to the mitotic cell cycle in the heart, lung, and kidneys. Our study provides the first exploratory, systematic look into the biological impact of the microRNAs associated with COVID-19, providing a new perspective for understanding its multiorgan physiopathology.

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Multi-omics evaluation of SARS-CoV-2 infected mouse lungs reveals dynamics of host responses

Cited by 7 publications

References 91 publications

Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals

Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals

SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis

Gene Network Analysis of the Transcriptome Impact of SARS-CoV-2 Interacting MicroRNAs in COVID-19 Disease

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