Dataset Information

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

ABSTRACT: Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a "cytokine storm." Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate the central role of Tim-1 in EBOV pathogenesis, as Tim-1-/- mice exhibited increased survival rates and reduced disease severity; surprisingly, only a limited decrease in viremia was detected. Tim-1-/- mice exhibited a modified inflammatory response as evidenced by changes in serum cytokines and activation of T helper subsets. A series of in vitro assays based on the Tim-1 expression profile on T cells demonstrated that despite the apparent absence of detectable viral replication in T lymphocytes, EBOV directly binds to isolated T lymphocytes in a phosphatidylserine-Tim-1-dependent manner. Exposure to EBOV resulted in the rapid development of a CD4Hi CD3Low population, non-antigen-specific activation, and cytokine production. Transcriptome and Western blot analysis of EBOV-stimulated CD4+ T cells confirmed the induction of the Tim-1 signaling pathway. Furthermore, comparative analysis of transcriptome data and cytokine/chemokine analysis of supernatants highlight the similarities associated with EBOV-stimulated T cells and the onset of a cytokine storm. Flow cytometry revealed virtually exclusive binding and activation of central memory CD4+ T cells. These findings provide evidence for the role of Tim-1 in the induction of a cytokine storm phenomenon and the pathogenesis of EVD.IMPORTANCE Ebola virus infection is characterized by a massive release of inflammatory mediators, which has come to be known as a cytokine storm. The severity of the cytokine storm is consistently linked with fatal disease outcome. Previous findings have demonstrated that specific T-cell subsets are key contributors to the onset of a cytokine storm. In this study, we investigated the role of Tim-1, a T-cell-receptor-independent trigger of T-cell activation. We first demonstrated that Tim-1-knockout (KO) mice survive lethal Ebola virus challenge. We then used a series of in vitro assays to demonstrate that Ebola virus directly binds primary T cells in a Tim-1-phosphatidylserine-dependent manner. We noted that binding induces a cytokine storm-like phenomenon and that blocking Tim-1-phosphatidylserine interactions reduces viral binding, T-cell activation, and cytokine production. These findings highlight a previously unknown role of Tim-1 in the development of a cytokine storm and "immune paralysis."

SUBMITTER: Younan P

PROVIDER: S-EPMC5615193 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

Younan Patrick P Iampietro Mathieu M Nishida Andrew A Ramanathan Palaniappan P Santos Rodrigo I RI Dutta Mukta M Lubaki Ndongala Michel NM Koup Richard A RA Katze Michael G MG Bukreyev Alexander A

mBio 20170926 5

Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a "cytokine storm." Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate th ...[more]

PMID: 28951472

Similar Datasets

Project description:BackgroundThe coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.MethodsWe obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.ResultsCOVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.ConclusionsCaspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.

Project description:UnlabelledMultiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections.ImportanceFiloviruses, including Ebola and Marburg viruses, cause rapidly fatal diseases in humans and nonhuman primates. There are currently no approved vaccines or therapeutics for filovirus diseases. In general, the cellular entry step of viruses is one of the key mechanisms to develop antiviral strategies. However, the molecular mechanisms underlying the entry process of filoviruses have not been fully understood. In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for filovirus entry, interact in the intracellular vesicles where Ebola virus GP-mediated membrane fusion occurs and that this interaction is important for filovirus infection. We found that filovirus infection and GP-mediated membrane fusion in cultured cells were remarkably suppressed by treatment with a TIM-1-specific monoclonal antibody that interfered with the interaction between TIM-1 and NPC1. Our data provide new insights for the development of antiviral compounds that can be universally used against filovirus infections.

Dataset Information

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

Publications

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets