Systems analysis of interaction between p38/MAPK pathway and SARS-CoV-2
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183999 | GEO | 2022/01/21
REPOSITORIES: GEO
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Project description:SARS-CoV-2, the causative agent of the COVID-19 pandemic, drastically modifies infected cells in an effort to optimize virus replication. Included in this process is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammation and is a central driver of COVID-19 clinical presentations. Inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduces both cytokine production and viral replication. Here, we combined genetic screening with quantitative phosphoproteomics to better understand interactions between the p38/MAPK pathway and SARS-CoV-2. We found several components of the p38/MAPK pathway impact SARS-CoV-2 replication and that p38β is a critical host factor that promotes viral replication and prevents activation of the interferon pathway. Quantitative phosphoproteomics uncovered several SARS-CoV-2 nucleocapsid (N) protein phosphorylation sites near the N-terminus that were sensitive to p38 inhibition. Similar to p38β depletion, mutation of these N residues was associated with reduced viral replication and increased activation of Type I interferon signaling. Taken together, this study reveals a unique proviral function for p38β that is not shared with p38α, and supports efforts to develop p38β inhibitors as a strategy towards developing a new class of COVID-19 therapies. methods
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Project description:A recombinant SARS-CoV lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major virulence determinant in vivo. Elimination of SARS-CoV E protein PBM by using reverse genetics led to attenuated viruses (SARS-CoV-mutPBM) and to a reduction in the deleterious exacerbate immune response triggered during infection with the parental virus (SARS-CoV-wt). Cellular protein syntenin bound E protein PBM during SARS-CoV infection. Syntenin activates p38 MAPK leading to overexpression of inflammatory cytokines, and we have shown that active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM (SARS-CoV-mutPBM) as compared with the parental virus (SARS-CoV-wt), leading to a decreased expression of inflammatory cytokines and to viral attenuation. Therefore, E protein PBM is a virulence factor that activates pathogenic immune response most likely by using syntenin as a mediator of p38 MAPK induced inflammation. Three biological replicates were independently hybridized (one channel per slide) for each sample type (SARS-CoV-wt, SARS-CoV-mutPBM, Mock). Slides were Sure Print G3 Agilent 8x60K Mouse (G4852A-028005)
2014-10-31 | E-GEOD-52920 | biostudies-arrayexpress
Project description:COVID-19 is a pandemic that shares only certain clinical characteristics with other acute viral infections. Here, we studied the whole-blood transcriptomic host response to SARS-CoV-2 and compared it with other viral infections to understand similarities and differences in host response. We profiled peripheral blood from 24 healthy controls and 62 prospectively enrolled patients with community-acquired lower respiratory tract infection by SARS-Cov-2 within the first 24 hours of hospital admission using RNA-seq. We also collected 23 independent studies that profiled 1,855 blood samples from patients with one of six viruses (influenza, RSV, HRV, Ebola, Dengue, and SARS). We identified differentially expressed genes that change in patients with COVID-19 or other viral infections. We show changes in gene expression in peripheral blood from patients with COVID-19 are highly correlated with changes in response to other viral infections (r=0.74, p<0.001). However, two genes, ACO1 and ATL3, show significantly different changes in expression. Pathway analysis of differentially expressed genes in patients with COVID-19 or other viral infections versus healthy controls also identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection, and cytokine production for over-expressed genes, as well as lymphocyte differentiation and T cell activation for under-expressed genes. When comparing transcriptome profiles of patients with COVID-19 directly with those with other viral infections, we found 114 and 302 genes were over- and under-expressed, respectively during COVID-19. Pathways analysis did not identify any significant pathways in these genes. Statistical deconvolution using immunoStates found that M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells, and total B cells showed changes consistently in the same direction across all viral infections including COVID-19. Those that increased in COVID-19 but decreased in non-COVID were CD56bright NK cells, M2 macrophages, and total NK cells. The concordant and discordant responses mapped out via such a comparison provides a window to explore the underlying biology of why COVID-19 is so different from other viral infections encountered so far. Together, results from pathway and immunoStates analyses help dissect major shifts in cellularity and activation of signaling pathways as part of host response to SARS-CoV-2
2020-12-10 | GSE152641 | GEO
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Project description:The on-going COVID-19 pandemic requires a deeper understanding of the long-term antibody responses that persist following SARS-CoV-2 infection. To that end, we determined epitope-specific IgG antibody responses in COVID-19 convalescent sera collected at 5 months post-diagnosis and compared that to sera from naïve individuals. Each serum sample was reacted with a high-density peptide microarray representing the complete proteome of SARS-CoV-2 as 15 mer peptides with 11 amino acid overlap and homologs of spike glycoprotein, nucleoprotein, membrane protein, and envelope small membrane protein from related human coronaviruses. Binding signatures were compared between COVID-19 convalescent patients and naïve individuals using the web service tool EPIphany.
2022-02-05 | E-MTAB-10740 | biostudies-arrayexpress
Project description:Viral pandemics pose an imminent threat to humanity. The ongoing COVID-19 pandemic, caused by the SARS-CoV-2 virus, requires the urgent development of anti-viral therapies. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here, we offer an in-depth analysis of the host response to SARS-CoV-2 as it compares to other respiratory infections. Cell and animal models of SARS-CoV-2 infections, in addition to transcriptional profiling of a COVID-19 lung biopsy consistently revealed a unique and inappropriate inflammatory response defined by elevated chemokine expression in the absence of Type I and III interferons. Our identification of a muted transcriptional response to SARS-CoV-2 supports a model in which initial failure to rapidly respond to infection results in prolonged viral replication and an influx of proinflammatory cells that induce alveolar damage and manifest in COVID-19 lung pathology.
2020-03-25 | GSE147507 | GEO
Project description:COVID-19 associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. It is unclear how susceptible human kidneys are to direct SARS-CoV-2 infection and whether pharmacologic manipulation of the renin-angiotensin II signaling (RAS) pathway modulates this susceptibility. Using induced pluripotent stem cell derived kidney organoids, SARS-CoV-1, SARS-CoV-2 and MERS-CoV tropism, defined by the paired expression of a host receptor (ACE2, NRP1 or DPP4) and protease (TMPRSS2, TMPRSS4, FURIN, CTSB or CTSL), was identified primarily amongst proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in COVID-19 patients, inhibited angiotensin II mediated internalization of ACE2, upregulated interferon stimulated genes (IFITM1 and BST2) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.
2022-01-23 | GSE149687 | GEO
Project description:It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlying molecular mechanism. RNA modification landscape of SARS-CoV-2 and its functional relevance to host cell innate immune response remain unknown. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigated m6A modification of SARS-CoV-2 gene in regulating host cell innate immune response. Our data showed that SARS-CoV-2 virus has m6A modification enriched in 3' region of the viral genome. We also found that host cell m6A methyltransferase METTL3 depletion reduced viral load in infected cells, decreased m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increased RIG-1 binding and subsequently enhanced downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in severe COVID-19 patients. These findings will aid to understand the COVID-19 pathogenesis and help in designing future studies of regulating innate immunity for COVID-19 treatment.
2021-04-27 | GSE167075 | GEO
Project description:Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the worldwide COVID-19 pandemic. While SARS-CoV-2 can infect people of all ages and both sexes, senior populations are at greatest risk of severe disease and worse outcomes, and sexual dimorphism has been reported in COVID-19. COVID-19 causes damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with Covid-19, with many survivors suffering from persistent neurological impairment, potentially accelerating Alzheimer’s disease (AD). This study aims to investigate the mechanisms underlying the impact of age, and sex on neuroinflammation due to SARS-CoV-2 infection using mouse models. Methods: Wild-type C57BL/6 mice were subjected to intranasal inoculation of SARS-CoV-2 lineage B.1.351, followed by daily body weight monitoring. At 7 dpi, viral burden and inflammatory cytokine/chemokine responses in the lung and brain were determined by quantitative RT-PCR, followed by immunohistochemical and transcriptomic analyses. Results: Older age, male sex, showed increased lung viral loads and severity of SARS-CoV-2 infection in mice. No viral RNA was detected in the brains of infected mice; however, IL-6 and CCL2 mRNA increased significantly, particularly in brains of old and APOE4 mice. Unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, and pathway analysis identified innate immunity and defense response to virus and other organisms as the major molecular networks affected in the brain by SARS-CoV-2 infection. Conclusions: Our findings demonstrate that age, and sex, modify the progression and outcome of SARS-CoV-2 infection. SARS-CoV-2 infection triggers neuroinflammatory responses despite the lack of detectable virus in the brain. Changes in molecular networks of innate immunity and defense response to microorganisms underlie the impact of SARS-CoV-2 infection in the brain. These findings in mice mimic epidemiological and clinical observations in humans with Covid-19.
2023-09-06 | GSE237092 | GEO
Project description:The SARS-CoV-2 virus has already caused over a million COVID-19 cases and over fifty-thousand deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 virus using human disease-relevant cells and tissues to understand key features of virus biology. We present a platform comprised of nine different cell and organoid derivatives from human pluripotent stem cells (hPSCs) representing all three primary germ layers, including lung progenitors and alveolar type II (AT2) cells, pancreatic endocrine cells, liver organoids, endothelial cells, cardiomyocytes, macrophages, microglia, and both cortical and dopaminergic neurons. We systematically probed which cell types are permissive to SARS-CoV-2 infection. Human pancreatic beta cells and hepatocytes were strikingly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and liver organoids. Both in vitro and in a humanized mouse model, human lung progenitors and AT2 cells express the ACE2 viral receptor and were highly permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection of hPSC-derived pancreatic and lung organoids revealed upregulation of chemokines but not type I/III interferon signaling, similar to what was seen in primary human COVID-19 pulmonary infection. Therefore, hPSC-derived cells phenocopy human COVID-19 disease and provide a valuable resource to understand SARS-CoV-2 biology and search for novel therapeutics.
2020-06-11 | GSE147903 | GEO