Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants
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ABSTRACT:
PROVIDER: PRJNA1255141 | ENA |
REPOSITORIES: ENA
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Project description:Mycophenolic acid (MPA) is commonly used in immunosuppressive regimens following solid organ transplantation. We demonstrate that MPA treatment reproducibly inhibits the replication of a range of viruses, including severe respiratory syndrome coronavirus 2 (SARS-CoV-2).xlxs. Mechanistically, we identified cellular guanosine triphosphate pool depletion as a key mediator of this antiviral effect. Strikingly, this inhibition can be overcome which was correlated with the emergence of three breakthrough mutations in the SARS-CoV-2 genome (S P812R, ORF3 Q185H, and E S6L). Subsequent analyses confirmed that the combination of these mutations conferred accelerated replication kinetics, higher viral titres and more rapid onset of cytopathic effects, but not MPA resistance. Comparison of global transcriptional responses to infection highlighted dysregulation of specific cellular gene programs under MPA treatment prior to breakthrough mutation emergence. Together, these findings identify viral and host drivers of variant emergence under immunosuppression. They also advocate for close monitoring of immunosuppressed patients, where emergence of novel viral variants with a fitness advantage may arise.
2025-06-01 | GSE295532 | GEO
Project description:The effect of Mycophenolic acid on primary isolated human dermal microvascular endothelial (HDMVEC) and fibroblast cells as well as human glioblastoma brain tumor cell line (U87).
2008-06-25 | E-TABM-315 | biostudies-arrayexpress
Project description:COVID-19 vaccines are continuing to become more widely available, but accurate and rapid testing remains a crucial tool for slowing the spread of the SARS-CoV-2 virus. Although quantitative reverse transcription-polymerase chain reaction (qRT-PCR) remains the most prevalent testing methodology, numerous tests have been developed that are predicated on detection of the SARS-CoV-2 nucleocapsid protein, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay based approaches. The continuing emergence of SARS-CoV-2 variants has complicated these approaches, as both qRT-PCR and antigen detection methods can be prone to missing viral variants. In this study, we describe a number of cases with COVID-19 where we were unable to detect the expected peptide targets from clinical nasopharyngeal swab samples that are typically identifiable in a targeted mass spectrometric assay. Whole genome sequencing revealed that single nucleotide polymorphisms in the gene encoding the viral nucleocapsid protein led to sequence variants that were not monitored in the targeted assay. Small modifications to the LC-MS/MS method ensured detection of the variants of the target peptide. Additional nucleocapsid variants were detected by performing bottom-up proteomic analysis of whole viral genome sequenced samples. This study demonstrates the importance of considering variants of SARS-CoV-2 in the assay design and highlights the flexibility of mass spectrometry-based approaches to detect variants as they evolve.
2022-02-17 | PXD026795 | Pride
Project description:Sequencing of SARS-CoV-2 variants samples or isolates
| PRJEB47699 | ENA
Project description:Remdesivir-induced emergence of SARS-CoV2 variants in patients with prolonged infection
| PRJEB50471 | ENA
Project description:Mycophenolic Acid (MPA) is the active component of the immunosuppressant Mycophenolate Mofetil, a potent inhibitor of the inosine monophosphate dehydrogenase. Direct effects of MPA on podocytes remain largely unknown. In order to elucidate genes and pathways affected by the drug, cultured murine podocytes exposed to MPA were subjected to RNA sequencing (RNASeq) analysis. Untreated samples served as controls. The RNASeq of MPA treated podocytes identified 351 significantly affected genes (padj < 0.05; 130 downregulated / 221 upregulated). Gene Ontology-Term enrichment analysis outlined two major groups of terms of particular interest, namely actin associated terms and terms related to inflammatory cell death. In conclusion, MPA treatment has a substantial effect on the transcriptome of podocytes. Analysis of the sequencing data revealed several non-immune cell dependent areas in which MPA possibly has a favorable effect on podocytes.
2023-03-27 | E-MTAB-11702 | biostudies-arrayexpress
Project description:A key feature of RNA viruses, including SARS-CoV-2, is their high mutation rate, which allows them to develop resistance to vaccines and antiviral drugs targeting viral proteins. To overcome this downside, a strategy would be to target host factors, i.e. cell proteins required by the virus for its replication. However, it is still unclear whether cell responses induced by different SARS-CoV-2 variants are conserved and if the same core of host factors is exploited by different variants. We compared 3 variants of concern (VOC) that emerged during the first year of the pandemic and observed that the host transcriptional response was mostly conserved, differing only in the kinetics and magnitude. By CRISPR screening we identified the host genes required for infection by each VOC. These genes were associated with interferon and JAK/STAT pathway, autophagy, mTOR pathway, mitochondrial organisation and activity. Crucially, we failed to identify genes required by only one variant. We further validated our candidates with small molecules and repurposed FDA-approved drugs, which were effective against a novel variant emerged during the course of the study. We observed that SARS-CoV-2 infection induces a rapid spike in Reactive Oxygen Species (ROS) production, which can be targeted to block viral propagation. Our study identifies a core of host genes required for infection, and lays the foundation for general therapeutic strategies aimed at minimising emergence of novel resistant variants.
2024-10-10 | GSE207981 | GEO
Project description:Effect of mycophenolic acid on MPC-1 murine podocytes
| PRJEB52911 | ENA
Project description:The ancestral SARS-CoV-2 strain that initiated the Covid-19 pandemic at the end of 2019 has rapidly mutated into multiple variants of concern with variable pathogenicity and increasing immune escape strategies. However, differences in host cellular antiviral responses upon infection with SARS-CoV-2 variants remains elusive. Leveraging whole cell proteomics, we determined host signalling pathways that are differentially modulated upon infection with the clinical isolates of the ancestral SARS-CoV-2 B.1 and the variants of concern Delta and Omicron BA.1. Our findings illustrate alterations in the global host proteome landscape upon infection with SARS-CoV-2 variants and the resulting host immune responses. Additionally, viral proteome kinetics reveal declining levels of viral protein expression during Omicron BA.1 infection when compared to ancestral B.1 and Delta variants, consistent with its reduced replication rates. Moreover, molecular assays reveal deferral activation of specific host antiviral signalling upon Omicron BA.1 and BA.2 infection. Our study provides an overview of host proteome profile of multiple SARS-CoV-2 variants and brings forth a better understanding of the instigation of key immune signalling pathways causative for the differential pathogenicity of SARS-CoV-2 variants.
2023-05-10 | PXD037265 | Pride
Project description:In this study, the anti-severe acute respiratory syndrome coronavirus-2 (anti-SARS-CoV-2) activity of mycophenolic acid (MPA) and IMD-0354 was analyzed. These compounds were chosen based on their antiviral activities against other coronaviruses. Because they also inhibit dengue virus (DENV) infection, other anti-DENV compounds/drugs were also assessed. On SARS-CoV-2-infected VeroE6/TMPRSS2 monolayers, both MPA and IMD-0354, but not other anti-DENV compounds/drugs, showed significant anti-SARS-CoV-2 activity. Although MPA reduced the viral RNA level by only approximately 100-fold, its half maximal effective concentration was as low as 0.87 µ m, which is easily achievable at therapeutic doses of mycophenolate mofetil. MPA targets the coronaviral papain-like protease and an in-depth study on its mechanism of action would be useful in the development of novel anti-SARS-CoV-2 drugs.
| S-EPMC7362101 | biostudies-literature