Severe Fever with Thrombocytopenia Syndrome Virus Induces Lactylation of m6A Reader Protein YTHDF1 to Facilitate Viral Replication
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE256528 | GEO | 2024/12/18
REPOSITORIES: GEO
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Project description:Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), an emerging infectious pathogen with a high fatality rate, is an enveloped tripartite segmented single-stranded negative-sense RNA virus. SFTSV infection is characterized by suppressed host innate immunity, proinflammatory cytokine storm, failure of B cell immunity and robust viral replication. m6A modification has been shown to play a role in viral infections. However, interactions between m6A modification and SFTSV infection remain poorly understood. Through MeRIP-seq, we identify m6A modifications on SFTSV RNA. We show that YTHDF1 can bind to m6A modification sites on SFTSV, decreasing the stability of SFTSV RNA and reducing translation efficiency of SFTSV proteins. The SFTSV virulence factor NSs increases lactylation of YTHDF1 and YTHDF1 degradation, thus facilitating SFTSV replication. Our findings indicate that the SFTSV protein NSs induces lactylation to inhibit YTHDF1 as a countermeasure to host's YTHDF1-mediated degradation of m6A-marked viral mRNAs.
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Project description:Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the WHO most dangerous pathogens, has 12-30% fatality rates with a characteristic thrombocytopenia syndrome. With a majority of clinically diagnosed SFTSV patients older than ~50 years, age is a critical risk factor for SFTSV morbidity and mortality. Here, we report an age-dependent ferret model of SFTSV infection and pathogenesis that fully recapitulates the clinical manifestations of human infections. While young adult ferrets (≤2 years old) did not show any clinical symptoms and mortality, SFTSV-infected aged ferrets (≥4 years old) demonstrated severe thrombocytopenia, reduced white blood cells, and high fever with 93% mortality rate. Moreover, significantly higher viral load was observed in aged ferrets. Transcriptome analysis of SFTSV-infected young ferrets revealed strong interferon-mediated anti-viral signaling, whereas inflammatory immune responses were markedly upregulated and persisted in aged ferrets. Thus, this immunocompetent age-dependent ferret model should be useful for anti-SFTSV therapy and vaccine development.
2018-10-30 | GSE121911 | GEO
Project description:Dabie bandavirus, also termed as severe fever with thrombocytopenia syndrome virus (SFTSV), was first isolated in China in 2010. At this time, the virus was found to have spread to South Korea, Japan, and other countries. A high case fatality rate is reported for SFTS, ranging from 12–50% within various sources. Several omics for clinical studies among SFTS patients as well as studies of cultured SFTSV have attempted to characterize the relevant molecular biology and epidemiology of the disease. However, a global serum proteomics analysis among SFTS patients has not yet been reported to date. Thrombocytopenia and multiple organ failure are the major immediate causes of death among SFTS patients. In this study, serum proteomic changes related to thrombocytopenia, abnormal immune response, and inflammatory activation were documented in SFTS patients. These findings provide useful information forunderstanding the clinical manifestations of SFTS.
2022-10-13 | PXD033989 | Pride
Project description:Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne infectious disease caused by a new SFTS virus (SFTSV). Due to its 12%-50% high fatality rate and the possibility of pandemic transmission, as well as no specific antiviral drugs for the treatment so far, SFTSV has been listed as one of the top 10 priority infectious diseases by the World Health Organization. Currently, there are rare studies of transcriptomic analysis for the patients infected with SFTSV, which makes it difficult to deeply understand the life cyle and pathogenicity of this virus. To explore the differences of transcripts after SFTSV infection, we performed a longitudinal sampling study to systematically investigate the chronological changes of viral load and transcriptomic and epigenetic characterization using white blood cells from SFTSV patients. The results showed significant changes in the expression of some genes from onset to recovery of SFTSV infection. Moreover, these differentially expressed genes showed good consistency in the three patients at different stages of treatment, which may contribute to the pathophysiology of SFTSV and thus lead to a breakthrough in SFTSV therapy. Moreover, by m6A-seq, we found some genes that might be regulated by m6A. This study in transcript changes and RNA modification may open a brand new direction to our understanding of SFTSV and play an important role in the drugs discovery for effective treatment.
2021-08-05 | GSE165518 | GEO
Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.
2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress
Project description:N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of hepatoma spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSCs). Stem cell-specific conditional Ythdf1 knock-in (CKI) mice treated with diethylnitrosamine showed elevated tumor burden compared with wild type mice. YTHDF1 promoted CSC renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1 deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through a YTHDF1-m6A-NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC.
2024-01-11 | GSE252752 | GEO
Project description:Severe fever with thrombocytopenia syndrome (SFTS), a tickborne viral disease, has been identified in China, South Korea, and Japan since 2009. We found retrospective evidence of SFTS virus (SFTSV) infection in Vietnam, which suggests that SFTSV infections also occur in Vietnam, where the virus has not been known to be endemic.
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Project description:Severe fever with thrombocytopenia syndrome virus (SFTSV), a member of the Phlebovirus genus from the Bunyaviridae family endemic to China, is the causative agent of life-threatening severe fever with thrombocytopenia syndrome (SFTS), which features high fever and hemorrhage. Similar to other negative-sense RNA viruses, SFTSV encodes a nucleocapsid protein (NP) that is essential for viral replication. NP facilitates viral RNA encapsidation and is responsible for the formation of ribonucleoprotein complex. However, recent studies have indicated that NP from Phlebovirus members behaves in inhomogeneous oligomerization states. In the present study, we report the crystal structure of SFTSV NP at 2.8 Å resolution and demonstrate the mechanism by which it processes a ringshaped hexameric form to accomplish RNA encapsidation. Key residues essential for oligomerization are identified through mutational analysis and identified to have a significant impact on RNA binding, which suggests that correct formation of highly ordered oligomers is a critical step in RNA encapsidation. The findings of this work provide new insights into the discovery of new antiviral reagents for Phlebovirus infection.
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Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.
2024-09-20 | PXD047819 | Pride
Project description:Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus, SFTS virus (SFTSV), with fatal outcome developed in approximately 17% of the cases. Thrombocytopenia is a hallmark feature of SFTS, and associated with a higher risk of fatal outcome, however, the pathophysiological involvement of platelet in the clinical outcome of SFTS remained under-investigated. In the current study, by retrospectively analyzing 1538 confirmed SFTS patients, we observed that thrombocytopenia was associated with enhanced activation of the cytokine network and the vascular endothelium, also with a disturbed coagulation response. The platelet phenotypes were also extensively altered in the process of thrombocytopenia development of SFTS patients. More importantly, all these disturbed host responses were related to the severity of thrombocytopenia, thus were considered to play in a synergistic way to influence the disease outcome. Moreover, the clinical effect of platelet transfusion was assessed by comparing two groups of patients with or without receiving this therapy. As a result, we observed no therapy effect in altering frequencies of fatal outcome, clinical bleeding development, or dynamic change of platelet count during the hospitalization. It's suggested that platelet supplementation alone acted a minor role in improving disease outcome, therefore new therapeutic intervention to regulate host response should be proposed. The current results revealed some evidence of interrelationship between platelet count and clinical outcome of SFTS disease from the perspective of activation of the cytokine network, the vascular endothelium, and the coagulation/fibrinolysis system. These evaluations might help to attain a better understanding of the pathogenesis and therapy choice in SFTS.
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