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Moldovan A, Wagner F, Schumacher F, Wigger D, Kessie DK, Rühling M, Stelzner K, Tschertok R, Kersting L, Fink J, Seibel J, Kleuser B, Rudel T. Chlamydia trachomatis exploits sphingolipid metabolic pathways during infection of phagocytes. mBio 2025; 16:e0398124. [PMID: 40249190 PMCID: PMC12077188 DOI: 10.1128/mbio.03981-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/19/2025] [Indexed: 04/19/2025] Open
Abstract
Chlamydiae are obligate intracellular pathogens that utilize host cell metabolites for catabolic and anabolic processes. The bacteria replicate in epithelial cells from which they take up sphingolipids (SL) and incorporate them into the chlamydial membrane and the vacuole (termed inclusion). SL uptake is essential for Chlamydia trachomatis (Ctr) in epithelial cells; however, they can also infect phagocytes, but the consequences for the SL metabolism have not yet been investigated in these cells. We performed a quantitative sphingolipidome analysis of infected primary neutrophils, macrophages, and immortalized fallopian tube epithelial cells. Sphingosine (Sph) levels are elevated in primary M2-like macrophages and human neutrophils infected with C. trachomatis. Human neutrophils respond to the pathogen by markedly upregulating sphingosine kinase 1 (SPHK1). We show in M2-like macrophages, by RNAseq, that two counteracting pathways involving upregulation of SPHK1, but also sphingosine-1-phosphate phosphatases 1 and 2 (SGPP1 and SGPP2) and sphingosine-1-phosphate lyase (SGPL1), maintain a steady pool of S1P. Using click chemistry, we show that exogenously added sphingomyelin (SM) and ceramide (Cer) are efficiently taken up into the chlamydial inclusion and are integrated into bacterial membranes in infected M2-like macrophages. Exogenous Sph reduces chlamydial infectivity, is transported into the inclusion lumen, and integrates into chlamydial membranes, suggesting that this particular SL species could represent a host defense mechanism. Taken together, our data indicate an important role for Sph/Sph kinase vs S1P/S1P phosphatase balance in infected phagocytes and a previously unrecognized role for sphingosine in the immune defense against chlamydial infection.IMPORTANCEChlamydia trachomatis (Ctr) is the leading cause of sexually transmitted diseases worldwide. Left untreated, it can cause severe complications such as blindness, pelvic inflammatory disease, or infertility. To date, no vaccines are available, and antibiotic treatment represents the only therapeutic approach to cure the infection. Limited access to antibiotics and displaced antibiotic intake increase the risk of developing recurring infections. Immune cells which fail to clear the infection and serve as a niche for chlamydial survival and replication, favor this outcome. Our research aims to elucidate the influence of sphingolipids (SL) during chlamydial infection, especially of phagocytic cells. Identifying relevant targets offers new strategies to develop alternative treatment methods.
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Affiliation(s)
- Adriana Moldovan
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabienne Wagner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Dominik Wigger
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - David Komla Kessie
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Marcel Rühling
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Kathrin Stelzner
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Regina Tschertok
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
| | - Louise Kersting
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Julian Fink
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Jürgen Seibel
- Institute of Organic Chemistry, University of Würzburg, Würzburg, Bavaria, Germany
| | - Burkhard Kleuser
- Institute of Pharmacy, Freie Universität Berlin, Berlin, Berlin, Germany
| | - Thomas Rudel
- Department of Microbiology, University of Würzburg, Würzburg, Bavaria, Germany
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Wang S, Mahalingam S, Merits A. Alphavirus nsP2: A Multifunctional Regulator of Viral Replication and Promising Target for Anti-Alphavirus Therapies. Rev Med Virol 2025; 35:e70030. [PMID: 40064592 PMCID: PMC11893376 DOI: 10.1002/rmv.70030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 02/19/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025]
Abstract
Alphaviruses are re-emerging vector-born pathogens that cause arthralgia or encephalitic diseases on a global scale. While a vaccine against chikungunya virus was recently approved, no vaccines currently exist for other alphaviruses, nor are there antiviral drugs for the treatment of alphavirus infections. Alphaviruses have positive-strand RNA genomes, and their RNA replication is coordinated by activities of the multifunctional nonstructural protein 2 (nsP2), a helicase-protease and a subunit of viral RNA replicase. We provide a comprehensive overview of nsP2 functions and inhibitors of its activities for their potential as effective antivirals. Furthermore, analysis of nsP2 activities suggests that it could be targeted to develop advanced live attenuated vaccines and strategies for controlling alphavirus transmission by mosquito vectors.
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Affiliation(s)
- Sainan Wang
- Institute of BioengineeringUniversity of TartuTartuEstonia
| | - Suresh Mahalingam
- Institute for Biomedicine and GlycomicsGriffith UniversityGold CoastAustralia
- Global Virus Network (GVN) Centre of Excellence in ArbovirusesGriffith UniversityGold CoastAustralia
- School of Pharmacy and Medical SciencesGriffith UniversityGold CoastAustralia
| | - Andres Merits
- Institute of BioengineeringUniversity of TartuTartuEstonia
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Hippee CE, Durnell LA, Kaufman JW, Murray E, Singh BK, Sinn PL. Epithelial-to-mesenchymal transition and live cell extrusion contribute to measles virus release from human airway epithelia. J Virol 2025; 99:e0122024. [PMID: 39791903 PMCID: PMC11852777 DOI: 10.1128/jvi.01220-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/13/2024] [Indexed: 01/12/2025] Open
Abstract
Measles virus (MeV) is a highly contagious respiratory virus transmitted via aerosols. To understand how MeV exits the airways of an infected host, we use unpassaged primary cultures of human airway epithelial cells (HAE). MeV typically remains cell-associated in HAE and forms foci of infection, termed infectious centers, by directly spreading cell-to-cell. We previously described the phenomenon in which infectious centers detach en masse from HAE and remain viable. Here, we investigate the mechanism of this cellular detachment. Via immunostaining, we observed loss of tight junction and cell adhesion proteins within infectious centers. These morphological changes indicate activation of epithelial-to-mesenchymal transition (EMT). EMT can contribute to wound healing in respiratory epithelia by mobilizing nearby cells. Inhibiting TGF-β, and thus EMT, reduced infectious center detachment. Compared with uninfected cells, MeV-infected cells also expressed increased levels of sphingosine kinase 1 (SK1), a regulator of live cell extrusion. Live cell extrusion encourages cells to detach from respiratory epithelia by contracting the actomyosin of neighboring cells. Inhibition or induction of live cell extrusion impacted infectious center detachment rates. Thus, these two related pathways contributed to infectious center detachment in HAE. Detached infectious centers contained high titers of virus that may be protected from the environment, allowing the virus to live on surfaces longer and infect more hosts.IMPORTANCEMeasles virus (MeV) is an extremely contagious respiratory pathogen that continues to cause large, disruptive outbreaks each year. Here, we examine mechanisms of detachment of MeV-infected cells. MeV spreads cell-to-cell in human airway epithelial cells (HAE) to form groups of infected cells, termed "infectious centers". We reported that infectious centers ultimately detach from HAE as a unit, carrying high titers of virus. Viral particles within cells may be more protected from environmental conditions, such as ultraviolet radiation and desiccation. We identified two host pathways, epithelial-to-mesenchymal transition and live cell extrusion, that contribute to infectious center detachment. Perturbing these pathways altered the kinetics of infectious center detachment. These pathways influence one another and contribute to epithelial wound healing, suggesting that infectious center detachment may be a usurped consequence of the host's response to infection that benefits MeV by increasing its transmissibility between hosts.
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Affiliation(s)
- Camilla E. Hippee
- Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Lorellin A. Durnell
- Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Justin W. Kaufman
- Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Eileen Murray
- Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Brajesh K. Singh
- Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
| | - Patrick L. Sinn
- Microbiology and Immunology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
- Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
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Ji W, Dang D, Zhou G, Tao L, Sun T, Li D, Cheng C, Feng H, Long J, Chen S, Yang H, Duan G, Jin Y. Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection. Antimicrob Agents Chemother 2025; 69:e0127224. [PMID: 39692504 PMCID: PMC11823611 DOI: 10.1128/aac.01272-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/03/2024] [Indexed: 12/19/2024] Open
Abstract
Hand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.
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Affiliation(s)
- Wangquan Ji
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Dejian Dang
- Department of Infection Control, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guangyuan Zhou
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ling Tao
- School of Public Health, Xinxiang Medical University, Xinxiang, Henan, China
| | - Tiantian Sun
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Dong Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Cheng Cheng
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Huifen Feng
- Department of Infection Control, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jinzhao Long
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Haiyan Yang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
| | - Yuefei Jin
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- Pingyuan Laboratory, Xinxiang, China
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Xiong Y, Ye Q, Liu L, Lin W, Liao Y, Gao R, Xu J, Zhang X, Chen R, Chen S, Chen Q, Wei L. The compensatory enrichment of sphingosine-1-phosphate on HDL in FSGS enhances the protective function of glomerular endothelial cells compared to MCD. Sci Rep 2025; 15:1530. [PMID: 39789110 PMCID: PMC11718056 DOI: 10.1038/s41598-025-85865-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 01/07/2025] [Indexed: 01/12/2025] Open
Abstract
Glomerular endothelial cells (GECs) are pivotal in developing glomerular sclerosis disorders. The advancement of focal segmental glomerulosclerosis (FSGS) is intimately tied to disruptions in lipid metabolism. Sphingosine-1-phosphate (S1P), a molecule transported by high-density lipoproteins (HDL), exhibits protective effects on vascular endothelial cells by upregulating phosphorylated endothelial nitric oxide synthase (p-eNOS) and enhancing nitric oxide (NO) production. Nevertheless, the abundance of S1P within HDL in individuals with FSGS and minimal change disease (MCD) is yet to be elucidated, and its defensive role in GECs necessitates empirical confirmation. A total of 14 FSGS patients, 16 MCD patients, and 16 healthy controls (NC) were included in the study, with FSGS and MCD confirmed by renal biopsy. After blood sample collection, HDL was isolated and categorized into intact HDL, phospholipid-depleted HDL(apo-HDL), phospholipid-remained HDL(phoHDL), and recombinant HDL (rHDL). Various HDL samples, comprising intact, apo-HDL, pho-HDL and rHDL, were co-cultivated with human renal glomerular endothelial cells (HRGECs). Western blotting was utilized to quantify p-eNOS levels and assess PI3K-AKT pathway activation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed S1P concentrations, while real-time quantitative PCR evaluated the expression of enzymes involved in S1P metabolism. Fluorescence labeling methods measured NO levels, and an immunofluorescence colocalization assay investigated Sphingosine-1-phosphate receptor 1 (S1PR1) expression in GECs across distinct kidney tissue groups. The HDL from FSGS patients demonstrated a significantly enhanced ability to promote p-eNOS expression and NO release in HRGECs compared to MCD patients and healthy controls. Additionally, the synthesis activity of S1P in renal tissues of FSGS patients was markedly higher than that observed in MCD patients and healthy controls, suggesting that S1P may play a crucial protective role in the progression of FSGS. Immunofluorescence staining showed that compared with MCD and NC, the expression of S1PR1 in GECs of FSGS patients was significantly decreased. Recombinant HDL with added S1P promoted the increase of p-eNOS in HRGECs. Knockdown of S1PR1 using siRNA reduced the expression of p-eNOS and NO release. The mechanism underlying the regulation of p-eNOS expression by rHDL was associated with the PI3K-AKT signaling pathway. The enhanced presence of S1P on HDL could serve as a diagnostic marker to differentiate FSGS from MCD. Incorporating S1P into HDL enhances glomerular endothelial cell function, suggesting that the S1P/S1PR pathway might offer a promising therapeutic avenue for FSGS.
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Affiliation(s)
- Yunfeng Xiong
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Qiuping Ye
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Lifang Liu
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Wanjun Lin
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Yonggen Liao
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China
| | - Ruiyu Gao
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jiaming Xu
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Xinyu Zhang
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ruoyan Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Sihui Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Qiaoling Chen
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China.
| | - Lixin Wei
- Department of Nephrology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
- Fujian Institute of Clinical Immunology, Fuzhou, 350001, China.
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Zhou M, Huang F, Du X, Liu G, Wang C. Analysis of the Differentially Expressed Proteins in Donkey Milk in Different Lactation Stages. Foods 2023; 12:4466. [PMID: 38137269 PMCID: PMC10742469 DOI: 10.3390/foods12244466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Proteins in donkey milk (DM) have special biological activities. However, the bioactive proteins and their expression regulation in donkey milk are still unclear. Thus, the differentially expressed proteins (DEPs) in DM in different lactation stages were first investigated by data-independent acquisition (DIA) proteomics. A total of 805 proteins were characterized in DM. The composition and content of milk proteins varied with the lactation stage. A total of 445 candidate DEPs related to biological processes and molecular functions were identified between mature milk and colostrum. The 219 down-regulated DEPs were mainly related to complement and coagulation cascades, staphylococcus aureus infection, systemic lupus erythematosus, prion diseases, AGE-RAGE signaling pathways in diabetic complications, and pertussis. The 226 up-regulated DEPs were mainly involved in metabolic pathways related to nutrient (fat, carbohydrate, nucleic acid, and vitamin) metabolism. Some other DEPs in milk from the lactation period of 30 to 180 days also had activities such as promoting cell proliferation, promoting antioxidant, immunoregulation, anti-inflammatory, and antibacterial effects, and enhancing skin moisture. DM can be used as a nutritional substitute for infants, as well as for cosmetic and medical purposes. Our results provide important insights for understanding the bioactive protein differences in DM in different lactation stages.
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Affiliation(s)
- Miaomiao Zhou
- School of Agricultural Science and Engineering, Liaocheng Research Institute of Donkey High-Efficiency Breeding and Ecological Feeding, Liaocheng University, Liaocheng 252000, China (C.W.)
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Mohammed S, Bindu A, Viswanathan A, Harikumar KB. Sphingosine 1-phosphate signaling during infection and immunity. Prog Lipid Res 2023; 92:101251. [PMID: 37633365 DOI: 10.1016/j.plipres.2023.101251] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/28/2023]
Abstract
Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.
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Affiliation(s)
- Sabira Mohammed
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India
| | - Anu Bindu
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India
| | - Arun Viswanathan
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India; Manipal Academy of Higher Education (MAHE), Manipal 576104, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala State 695014, India.
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Al-Kuraishy HM, Batiha GES, Al-Gareeb AI, Al-Harcan NAH, Welson NN. Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon. Mol Cell Biochem 2023; 478:2271-2279. [PMID: 36652045 PMCID: PMC9848039 DOI: 10.1007/s11010-023-04658-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023]
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, immunity, angiogenesis, vascular permeability, and lymphocyte trafficking through G-protein coupled S1P receptors. Reduction of the circulating S1P level correlates with COVID-19 severity. S1P binding to sphingosine-1-phosphate receptor 1 (S1PR1) elicits endothelial protection and anti-inflammatory effects during SARS-CoV-2 infection, by limiting excessive INF-α response and hindering mitogen-activated protein kinase and nuclear factor kappa B action. However, binding to S1PR2 opposes the effect of S1PR1 with vascular inflammation, endothelial permeability, and dysfunction as the concomitant outcome. This binding also promotes nod-like receptor pyrin 3 (NLRP3) inflammasome activation, causing liver inflammation and fibrogenesis. Thus, higher expression of macrophage S1PR2 contributes to the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines. In conclusion, S1PR1 agonists and S1PR2 antagonists might effectively manage COVID-19 and its severe effects. Further studies are recommended to elucidate the potential conflict in the effects of S1P in COVID-19.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
| | - Nasser A Hadi Al-Harcan
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Rasheed University College, Baghdad, Iraq
| | - Nermeen N Welson
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt.
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Kamal AHM, Chakrabarty JK, Chowdhury SM. Lipopolysaccharide and statin-mediated immune-responsive protein networks revealed in macrophages through affinity purification spacer-arm controlled cross-linking (AP-SPACC) proteomics. Mol Omics 2023; 19:48-59. [PMID: 36377691 DOI: 10.1039/d2mo00224h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Toll-like receptor 4 (TLR4), a pattern recognition receptor, is activated by lipopolysaccharides (LPS) and induces the MyD88 pathway, which subsequently produces pro-inflammatory cytokines through activation of transcriptional nuclear factor (NF)-κB. Statins have been widely prescribed to reduce cholesterol synthesis for patients with cardiovascular disease. Statins may have pleiotropic effects, which include anti- and pro-inflammatory effects on cells. The molecular mechanism of the sequential influence of LPS and statin on the innate immune system remains unknown. We employed affinity purification-spacer-arm controlled cross-linking (AP-SPACC) MS-based proteomics analysis to identify the LPS- and statin-LPS-responsive proteins and their networks. LPS-stimulated RAW 264.7 macrophage cells singly and combined with the drug statin used in this study. Two chemical cross-linkers with different spacer chain lengths were utilized to stabilize the weak and transient interactors. Proteomic analysis identified 1631 differentially expressed proteins. We identified 151 immune-response proteins through functional enrichment analysis and visualized their interaction networks. Selected candidate protein-coding genes were validated, specifically squamous cell carcinoma antigens recognized by T cells 3, sphingosine-1-phosphate lyase 1, Ras-related protein Rab-35, and tumor protein D52 protein-coding genes through transcript-level expression analysis. The expressions of those genes were significantly increased upon statin treatment and decreased in LPS-stimulated macrophage cells. Therefore, we presumed that the expression changes of genes occurred due to immune response during activation of inflammation. These results highlight the immune-responsive proteins network, providing a new platform for novel investigations and discovering future therapeutic targets for inflammatory diseases.
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Affiliation(s)
- Abu Hena Mostafa Kamal
- Department of Chemistry and Biochemistry, University of Texas at Arlington, TX, 76019, USA. .,Advanced Technology Cores, Dan L Duncan Comprehensive Cancer Center, Metabolomics Core, Baylor College of Medicine, Houston, TX, 77030, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jayanta K Chakrabarty
- Department of Chemistry and Biochemistry, University of Texas at Arlington, TX, 76019, USA. .,Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY, 10027, USA
| | - Saiful M Chowdhury
- Department of Chemistry and Biochemistry, University of Texas at Arlington, TX, 76019, USA.
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Beyoğlu D, Schwalm S, Semmo N, Huwiler A, Idle JR. Hepatitis C Virus Infection Upregulates Plasma Phosphosphingolipids and Endocannabinoids and Downregulates Lysophosphoinositols. Int J Mol Sci 2023; 24:ijms24021407. [PMID: 36674922 PMCID: PMC9864155 DOI: 10.3390/ijms24021407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/04/2023] [Accepted: 01/08/2023] [Indexed: 01/12/2023] Open
Abstract
A mass spectrometry-based lipidomic investigation of 30 patients with chronic hepatitis C virus (HCV) infection and 30 age- and sex-matched healthy blood donor controls was undertaken. The clustering and complete separation of these two groups was found by both unsupervised and supervised multivariate data analyses. Three patients who had spontaneously cleared the virus and three who were successfully treated with direct-acting antiviral drugs remained within the HCV-positive metabotype, suggesting that the metabolic effects of HCV may be longer-lived. We identified 21 metabolites that were upregulated in plasma and 34 that were downregulated (p < 1 × 10-16 to 0.0002). Eleven members of the endocannabinoidome were elevated, including anandamide and eight fatty acid amides (FAAs). These likely activated the cannabinoid receptor GPR55, which is a pivotal host factor for HCV replication. FAAH1, which catabolizes FAAs, reduced mRNA expression. Four phosphosphingolipids, d16:1, d18:1, d19:1 sphingosine 1-phosphate, and d18:0 sphinganine 1-phosphate, were increased, together with the mRNA expression for their synthetic enzyme SPHK1. Among the most profoundly downregulated plasma lipids were several lysophosphatidylinositols (LPIs) from 3- to 3000-fold. LPIs are required for the synthesis of phosphatidylinositol 4-phosphate (PI4P) pools that are required for HCV replication, and LPIs can also activate the GPR55 receptor. Our plasma lipidomic findings shed new light on the pathobiology of HCV infection and show that a subset of bioactive lipids that may contribute to liver pathology is altered by HCV infection.
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Affiliation(s)
- Diren Beyoğlu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA
- Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland
| | - Stephanie Schwalm
- Pharmazentrum Frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, D-60590 Frankfurt am Main, Germany
- Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland
| | - Nasser Semmo
- Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland
| | - Andrea Huwiler
- Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland
- Correspondence: (A.H.); (J.R.I.)
| | - Jeffrey R. Idle
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA
- Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland
- Correspondence: (A.H.); (J.R.I.)
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11
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Cong D, Yu Y, Meng Y, Qi X. Dexmedetomidine (Dex) exerts protective effects on rat neuronal cells injured by cerebral ischemia/reperfusion via regulating the Sphk1/S1P signaling pathway. J Stroke Cerebrovasc Dis 2023; 32:106896. [PMID: 36395661 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106896] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/27/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
AIM To investigate the influence of dexmedetomidine (Dex) on cerebral ischemia/reperfusion (I/R)-injured rat neuronal cells by regulating the Sphk1/S1P pathway. METHODS The rats were divided into the following groups, with 18 rats in each group categorized on the basis of random number tables: sham (Sham), I/R (I/R), Dex, Sphk1 inhibitor (PF-543), and Dex together with the Sphk1 agonist phorbol-12-myristate-13-acetate (Dex+PMA). The neurological functions of the rats were assessed by the Longa scoring system at 24 h post reperfusion. The area of brain infarction was inspected using 2,3,5-triphenyltetrazolium chloride staining, and the water content of brain tissue was determined by the dry-wet weight method. The morphology of neurons in the CA1 region of the rat hippocampus was inspected using Nissl staining, while the apoptosis of neurons in this region was detected by terminal-deoxynucleotidyl transferase mediated nick end labeling staining. The Sphk1 and S1P protein levels were determined by immunofluorescence and western blotting, respectively. RESULTS Compared to the I/R group, rats in the Dex, PF-543, and Dex+PMA groups had a significantly lower neurological function score, as well as lower brain water content and a decreased infarction area. Moreover, the apoptotic index of the neurons and the Sphk1 and S1P levels in the hippocampal CA1 region were significantly lower in these groups (p<0.05). PMA, an agonist of Sphk1, was able to reverse the protective effects of Dex on I/R-induced neuronal cell injury. CONCLUSION Dex could protect cerebral I/R-induced neuronal cell injury by suppressing the Sphk1/S1P signaling pathway.
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Affiliation(s)
- Dawei Cong
- Department of Neurosurgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai 264100, China
| | - Yunlong Yu
- Department of Neurosurgery, Yantai Harbour Hospital, Yantai 264000, China.
| | - Yan Meng
- Yantai Comprehensive Health Service Center, Yantai 264000, China
| | - Xia Qi
- Yantai Comprehensive Health Service Center, Yantai 264000, China
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12
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Effect of the Interaction between Viral PB2 and Host SphK1 on H9N2 AIV Replication in Mammals. Viruses 2022; 14:v14071585. [PMID: 35891566 PMCID: PMC9322132 DOI: 10.3390/v14071585] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 01/25/2023] Open
Abstract
The H9N2 avian influenza virus (AIV) is currently widespread worldwide, posing a severe threat to the poultry industry and public health. Reassortment is an important way for influenza viruses to adapt to a new host. In 2007, the PB2 gene of H9N2 AIV in China was reassorted, and the DK1-like lineage replaced the F/98-like lineage, forming a dominant genotype of G57. This genotype and its reassortants (such as H7N9, H10N8 and H5N6) showed higher mammalian adaptation, and caused increased human infections. However, the adaptive mechanisms of the DK1-like lineage PB2 gene remain unclear. Here, we confirmed that the PB2 lineage of the H9N2 AIV currently prevalent in China still belongs to the DK1-like lineage and, compared with the previously predominant F/98-like lineage, the DK1-like lineage PB2 gene significantly enhances H9N2 AIV to mammalian adaptation. Through transcriptomic analysis and qRT–PCR and western blot experiments, we identified a host factor, sphingosine kinase 1 (SphK1), that is closely related to viral replication. SphK1 inhibits the replication of DK1-like PB2 gene H9N2 AIV, but the ability of SphK1 protein to bind DK1-like PB2 protein is weaker than that of F/98-like PB2 protein, which may contribute to H9N2 AIV containing the DK1-like PB2 gene to escape the inhibitory effect of host factor SphK1 for efficient infection. This study broadens our understanding of the adaptive evolution of H9N2 AIV and highlights the necessity to pay close attention to the AIV that contains the adaptive PB2 protein in animals and humans.
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13
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Zhou Y, Pu J, Wu Y. The Role of Lipid Metabolism in Influenza A Virus Infection. Pathogens 2021; 10:303. [PMID: 33807642 PMCID: PMC7998359 DOI: 10.3390/pathogens10030303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/25/2021] [Accepted: 03/03/2021] [Indexed: 11/16/2022] Open
Abstract
Influenza A virus (IAV) is an important zoonotic pathogen that can cause disease in animals such as poultry and pigs, and it can cause infection and even death in humans, posing a serious threat to public health. IAV is an enveloped virus that relies on host cell metabolic systems, especially lipid metabolism systems, to complete its life cycle in host cells. On the other side, host cells regulate their metabolic processes to prevent IAV replication and maintain their normal physiological functions. This review summarizes the roles of fatty acid, cholesterol, phospholipid and glycolipid metabolism in IAV infection, proposes future research challenges, and looks forward to the prospective application of lipid metabolism modification to limit IAV infection, which will provide new directions for the development of anti-influenza drugs.
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Affiliation(s)
- Yong Zhou
- Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (Y.Z.); (J.P.)
| | - Juan Pu
- Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; (Y.Z.); (J.P.)
| | - Yuping Wu
- College of Life Science and Basic Medicine/Center for Biotechnology Research, Xinxiang University, Xinxiang 453003, China
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14
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Imre G, Krähling V, Eichler M, Trautmann S, Ferreirós N, Aman MJ, Kashanchi F, Rajalingam K, Pöhlmann S, Becker S, Meyer Zu Heringdorf D, Pfeilschifter J. The sphingosine kinase 1 activator, K6PC-5, attenuates Ebola virus infection. iScience 2021; 24:102266. [PMID: 33817572 PMCID: PMC8005759 DOI: 10.1016/j.isci.2021.102266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 02/08/2021] [Accepted: 03/01/2021] [Indexed: 12/18/2022] Open
Abstract
Ebola virus (EBOV) is responsible for outbreaks with case fatality rates of up to 90% and for an epidemic in West Africa with more than ten thousand deaths. EBOV glycoprotein (EBOV-GP) is the only viral surface protein and is responsible for viral entry into cells. Here, by employing pseudotyped EBOV-GP viral particles, we uncover a critical role for sphingolipids in inhibiting viral entry. Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). The administration of the SphK1 activator, K6PC-5, or S1P, or the overexpression of SphK1 consistently exhibited striking inhibitory effects in EBOV-GP-driven entry in diverse cell lines. Finally, K6PC-5 markedly reduced the EBOV titer in infected cells and the de novo production of viral proteins. These data present K6PC-5 as an efficient tool to inhibit EBOV infection in endothelial cells and suggest further studies to evaluate its systemic effects.
K6PC-5, a sphingosine kinase 1 activator, inhibits Ebola virus infection Sphingosine 1-phosphate, the product of SphK1, attenuates the viral entry Inhibiton/activation of S1P receptors has no influence on Ebola virus entry These data support the endogen effect of S1P in Ebola virus infection
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Affiliation(s)
- Gergely Imre
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Verena Krähling
- Institute of Virology, Philipps University Marburg, Marburg, Germany.,German Center for Infection Research (DZIF), partner site Gießen-Marburg-Langen, Marburg, Germany
| | - Madeleine Eichler
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Sandra Trautmann
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Nerea Ferreirós
- Institute of Clinical Pharmacology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - M Javad Aman
- Integrated BioTherapeutics, Inc., Gaithersburg, MD 20850, USA
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, George Mason University Manassas, VA 20110, USA
| | - Krishnaraj Rajalingam
- Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.,Faculty of Biology and Psychology, University Göttingen, 37077 Göttingen, Germany
| | - Stephan Becker
- Institute of Virology, Philipps University Marburg, Marburg, Germany.,German Center for Infection Research (DZIF), partner site Gießen-Marburg-Langen, Marburg, Germany
| | - Dagmar Meyer Zu Heringdorf
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
| | - Josef Pfeilschifter
- Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main 60590, Germany
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15
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Liu Y, Zhang Y, Wang M, Cheng A, Yang Q, Wu Y, Jia R, Liu M, Zhu D, Chen S, Zhang S, Zhao X, Huang J, Mao S, Ou X, Gao Q, Wang Y, Xu Z, Chen Z, Zhu L, Luo Q, Liu Y, Yu Y, Zhang L, Tian B, Pan L, Chen X. Structures and Functions of the 3' Untranslated Regions of Positive-Sense Single-Stranded RNA Viruses Infecting Humans and Animals. Front Cell Infect Microbiol 2020; 10:453. [PMID: 32974223 PMCID: PMC7481400 DOI: 10.3389/fcimb.2020.00453] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/23/2020] [Indexed: 12/20/2022] Open
Abstract
The 3′ untranslated region (3′ UTR) of positive-sense single-stranded RNA [ssRNA(+)] viruses is highly structured. Multiple elements in the region interact with other nucleotides and proteins of viral and cellular origin to regulate various aspects of the virus life cycle such as replication, translation, and the host-cell response. This review attempts to summarize the primary and higher order structures identified in the 3′UTR of ssRNA(+) viruses and their functional roles.
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Affiliation(s)
- Yuanzhi Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - XinXin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Juan Huang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Qun Gao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bin Tian
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Leichang Pan
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.,Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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16
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Graber K, Khan F, Glück B, Weigel C, Marzo S, Doshi H, Ehrhardt C, Heller R, Gräler M, Henke A. The role of sphingosine-1-phosphate signaling in HSV-1-infected human umbilical vein endothelial cells. Virus Res 2020; 276:197835. [DOI: 10.1016/j.virusres.2019.197835] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/06/2019] [Accepted: 12/06/2019] [Indexed: 01/14/2023]
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17
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Boxberger N, Hecker M, Zettl UK. Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases. THE JOURNAL OF IMMUNOLOGY 2019; 202:2177-2187. [PMID: 30962309 DOI: 10.4049/jimmunol.1801416] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 12/19/2018] [Indexed: 12/13/2022]
Abstract
Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1β and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics.
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Affiliation(s)
- Nina Boxberger
- Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany; and
| | - Michael Hecker
- Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany; and.,Steinbeis Transfer Center for Proteome Analysis, 18057 Rostock, Germany
| | - Uwe K Zettl
- Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany; and
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18
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Al-Shujairi WH, Clarke JN, Davies LT, Pitman MR, Calvert JK, Aloia AL, Pitson SM, Carr JM. In vitro and in vivo roles of sphingosine kinase 2 during dengue virus infection. J Gen Virol 2019; 100:629-641. [PMID: 30869582 DOI: 10.1099/jgv.0.001245] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
There is growing evidence of the influence of sphingosine kinase (SK) enzymes on viral infection. Here, the role of sphingosine kinase 2 (SK2), an isoform of SK prominent in the brain, was defined during dengue virus (DENV) infection. Chemical inhibition of SK2 activity using two different SK2 inhibitors, ABC294640 and K145, had no effect on DENV infection in human cells in vitro. In contrast, DENV infection was restricted in SK2-/- immortalized mouse embryonic fibroblasts (iMEFs) with reduced induction of IFN-β mRNA and protein, and mRNA for the IFN-stimulated genes (ISGs) viperin, IFIT1, IRF7 and CXCL10 in DENV-infected SK2-/- compared to WT iMEFs. Intracranial (ic) DENV injection in C57BL/6 SK2-/- mice induced body weight loss earlier than in WT mice but DENV RNA levels were comparable in the brain. Neither SK1 mRNA or sphingosine-1-phosphate (S1P) levels were altered following ic DENV infection in WT or SK2-/- mice but brain S1P levels were reduced in all SK2-/- mice, independent of DENV infection. CD8 mRNA was induced in the brains of both DENV-infected WT and SK2-/- mice, suggesting normal CD8+ T-cell infiltration into the DENV-infected brain independent of SK2 or S1P. Thus, although SK2 may be important for replication of some viruses SK2 activity does not affect DENV infection in vitro and SK2 or S1P levels do not influence DENV infection or T-cell infiltration in the context of infection in the brain.
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Affiliation(s)
- Wisam H Al-Shujairi
- 1Microbiology and Infectious Diseases, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, 5042, South Australia
- 2Department of Laboratory and Clinical Sciences, College of Pharmacy, University of Babylon, Hilla 51002, Iraq
| | - Jennifer N Clarke
- 1Microbiology and Infectious Diseases, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, 5042, South Australia
| | - Lorena T Davies
- 3Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5000, South Australia
| | - Melissa R Pitman
- 3Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5000, South Australia
| | - Julie K Calvert
- 1Microbiology and Infectious Diseases, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, 5042, South Australia
| | - Amanda L Aloia
- 4Cell Screen SA, Flinders University, Bedford Park, Adelaide, 5042, South Australia
| | - Stuart M Pitson
- 3Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, 5000, South Australia
| | - Jillian M Carr
- 1Microbiology and Infectious Diseases, College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, 5042, South Australia
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19
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Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation. J Invest Dermatol 2018; 139:807-817. [PMID: 30399362 DOI: 10.1016/j.jid.2018.10.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/21/2018] [Accepted: 10/23/2018] [Indexed: 01/01/2023]
Abstract
The majority of Merkel cell carcinoma, a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus infection. Polyomavirus binding, internalization, and infection are mediated by glycosphingolipids. Besides receptor function, bioactive sphingolipids are increasingly recognized as potent regulators of several hallmarks of cancer. Merkel cell polyomavirus+ and Merkel cell polyomavirus- cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomavirus-large tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK 1/2 expression. Therefore, we exploited pharmacological inhibition of sphingolipid metabolism as an option to interfere with proliferation of Merkel cell polyomavirus+ Merkel cell carcinoma cell lines. We used myriocin (a serine palmitoyl transferase antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate content. SKI-II increased ceramide species but decreased sphingomyelin and sphingosine-1-phosphate concentrations. Aberrant sphingolipid homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKTS473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of sphingolipid synthesis could represent a potential therapeutic approach in Merkel cell carcinoma.
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20
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Zilch A, Rien C, Weigel C, Huskobla S, Glück B, Spengler K, Sauerbrei A, Heller R, Gräler M, Henke A. Influence of sphingosine-1-phosphate signaling on HCMV replication in human embryonal lung fibroblasts. Med Microbiol Immunol 2018; 207:227-242. [DOI: 10.1007/s00430-018-0543-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 04/17/2018] [Indexed: 12/16/2022]
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Abstract
Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.
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22
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Aloia AL, Calvert JK, Clarke JN, Davies LT, Helbig KJ, Pitson SM, Carr JM. Investigation of sphingosine kinase 1 in interferon responses during dengue virus infection. Clin Transl Immunology 2017; 6:e151. [PMID: 28791126 PMCID: PMC5539417 DOI: 10.1038/cti.2017.32] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 06/13/2017] [Accepted: 06/13/2017] [Indexed: 02/06/2023] Open
Abstract
Dengue virus (DENV) regulates sphingosine kinase (SK)-1 activity and chemical inhibition of SK1 reduces DENV infection. In primary murine embryonic fibroblasts (pMEFs) lacking SK1 however, DENV infection is enhanced and this is associated with induction of normal levels of interferon beta (IFN-β) but reduced levels of IFN-stimulated genes (ISGs). We have further investigated this link between SK1 and type I IFN responses. DENV infection downregulates cell-surface IFN-alpha receptor (IFNAR)1 in both wild-type (WT) and SK1-/- pMEF, but, consistent with poor ISG responses, shows reduced induction of phosphorylated (p)-STAT1 and key IFN regulatory factors (IRF)1 and -7 in SK1-/- pMEF. Direct IFN stimulation induced ISGs (viperin, IFIT1), CXCL10, IRF1 and -7 and p-STAT1. Responses, however, were significantly reduced in SK1-/- pMEF, except for IFN-stimulated CXCL10 and IRF7. Poor IFN responses in SK1-/- pMEF were associated with a small reduction in basal cell-surface IFNAR1 and IRF1 mRNA in uninfected SK1-/- compared with WT pMEF. In contrast, treatment of cells with the SK1 inhibitor, SK1-I or expression of an inhibitory SK1 short hairpin RNA (shRNA), both of which reduce DENV infection, does not alter basal IRF1 mRNA or affect type I IFN stimulation of p-STAT1. Thus, cells genetically lacking SK1 can induce many responses normally following DENV infection, but have adaptive changes in IFNAR1 and IRF1 that compromise DENV-induced type I IFN responses. This suggests a biological link between SK1 and IFN-stimulated pathways. Other approaches to reduce SK1 activity, however, do not influence these important antiviral pathways but reduce infection and may be useful antiviral strategies.
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Affiliation(s)
- Amanda L Aloia
- Department of Microbiology and Infectious Diseases, School of Medicine, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
| | - Julie K Calvert
- Department of Microbiology and Infectious Diseases, School of Medicine, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
| | - Jennifer N Clarke
- Department of Microbiology and Infectious Diseases, School of Medicine, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
| | - Lorena T Davies
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Karla J Helbig
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Victoria, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Jillian M Carr
- Department of Microbiology and Infectious Diseases, School of Medicine, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
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23
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Punsawad C, Viriyavejakul P. Reduction in serum sphingosine 1-phosphate concentration in malaria. PLoS One 2017; 12:e0180631. [PMID: 28666023 PMCID: PMC5493422 DOI: 10.1371/journal.pone.0180631] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 06/19/2017] [Indexed: 11/29/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin which is involved in the endothelial permeability and inflammation. Although the plasma S1P concentration is reportedly decreased in patients with cerebral malaria, the role of S1P in malaria is still unclear. The purpose of this study was to examine the impact of malaria on circulating S1P concentration and its relationship with clinical data in malaria patients. Serum S1P levels were measured in 29 patients with P. vivax, 30 patients with uncomplicated P. falciparum, and 13 patients with complicated P. falciparum malaria on admission and on day 7, compared with healthy subjects (n = 18) as control group. The lowest level of serum S1P concentration was found in the complicated P. falciparum malaria group, compared with P. vivax, uncomplicated P. falciparum patients and healthy controls (all p < 0.001). In addition, serum S1P level was positively correlated with platelet count, hemoglobin and hematocrit levels in malaria patients. In conclusions, low levels of S1P are associated with the severity of malaria, and are correlated with thrombocytopenia and anemia. These findings highlight a role of S1P in the severity of malaria and support the use of S1P and its analogue as a novel adjuvant therapy for malaria complications.
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Affiliation(s)
- Chuchard Punsawad
- School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
- Tropical Diseases and Parasitic Infectious Diseases Research Group, Walailak University, Nakhon Si Thammarat, Thailand
| | - Parnpen Viriyavejakul
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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24
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Al-Shujairi WH, Clarke JN, Davies LT, Alsharifi M, Pitson SM, Carr JM. Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways. PLoS One 2017; 12:e0169814. [PMID: 28095439 PMCID: PMC5240945 DOI: 10.1371/journal.pone.0169814] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 12/21/2016] [Indexed: 02/05/2023] Open
Abstract
We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain.
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Affiliation(s)
- Wisam H. Al-Shujairi
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia
| | - Jennifer N. Clarke
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia
| | - Lorena T. Davies
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Mohammed Alsharifi
- Vaccine Research Laboratory, Research Centre for Infectious Diseases, and Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Stuart M. Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Jillian M. Carr
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia
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25
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Crespo I, San-Miguel B, Sánchez DI, González-Fernández B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin inhibits the sphingosine kinase 1/sphingosine-1-phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin. J Pineal Res 2016; 61:168-76. [PMID: 27101794 DOI: 10.1111/jpi.12335] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 04/19/2016] [Indexed: 01/08/2023]
Abstract
The sphingosine kinase (SphK)1/sphingosine-1-phosphate (S1P) pathway is involved in multiple biological processes, including liver diseases. This study investigate whether modulation of the SphK1/S1P system associates to the beneficial effects of melatonin in an animal model of acute liver failure (ALF) induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 × 10(4) hemagglutination units of a RHDV isolate and received 20 mg/kg of melatonin at 0, 12, and 24 hr postinfection. Liver mRNA levels, protein concentration, and immunohistochemical labeling for SphK1 increased in RHDV-infected rabbits. S1P production and protein expression of the S1PR1 receptor were significantly elevated following RHDV infection. These effects were significantly reduced by melatonin. Rabbits also exhibited increased expression of toll-like receptor (TLR)4, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, nuclear factor-kappa B (NF-κB) p50 and p65 subunits, and phosphorylated inhibitor of kappa B (IκB)α. Melatonin administration significantly inhibited those changes and induced a decreased immunoreactivity for RHDV viral VP60 antigen in the liver. Results obtained indicate that the SphK1/S1P system activates in parallel to viral replication and the inflammatory process induced by the virus. Inhibition of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in this animal model of ALF, and supports the potential of melatonin as an antiviral agent.
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Affiliation(s)
- Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Beatriz San-Miguel
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | | | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María J Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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26
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Kashem MA, Kennedy CA, Fogarty KE, Dimock JR, Zhang Y, Sanville-Ross ML, Skow DJ, Brunette SR, Swantek JL, Hummel HS, Swindle J, Nelson RM. A High-Throughput Genetic Complementation Assay in Yeast Cells Identified Selective Inhibitors of Sphingosine Kinase 1 Not Found Using a Cell-Free Enzyme Assay. Assay Drug Dev Technol 2016; 14:39-49. [DOI: 10.1089/adt.2015.671] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
- Mohammed A. Kashem
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Charles A. Kennedy
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Kylie E. Fogarty
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Janice R. Dimock
- Immunology and Respiratory Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Yunlong Zhang
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Mary L. Sanville-Ross
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Donna J. Skow
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Steven R. Brunette
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Jennifer L. Swantek
- Immunology and Respiratory Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | | | | | - Richard M. Nelson
- Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
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27
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Reiss CS. Innate Immunity in Viral Encephalitis. NEUROTROPIC VIRAL INFECTIONS 2016. [PMCID: PMC7153449 DOI: 10.1007/978-3-319-33189-8_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Carol Shoshkes Reiss
- Departments of Biology and Neural Science, New York University, New York, New York USA
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28
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Clarke JN, Davies LK, Calvert JK, Gliddon BL, Shujari WHA, Aloia AL, Helbig KJ, Beard MR, Pitson SM, Carr JM. Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses. J Gen Virol 2015; 97:95-109. [PMID: 26541871 DOI: 10.1099/jgv.0.000334] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Sphingosine kinase (SK) 1 is a host kinase that enhances some viral infections. Here we investigated the ability of SK1 to modulate dengue virus (DENV) infection in vitro. Overexpression of SK1 did not alter DENV infection; however, targeting SK1 through chemical inhibition resulted in reduced DENV RNA and infectious virus release. DENV infection of SK1⁻/ ⁻ murine embryonic fibroblasts (MEFs) resulted in inhibition of infection in an immortalized line (iMEF) but enhanced infection in primary MEFs (1°MEFs). Global cellular gene expression profiles showed expected innate immune mRNA changes in DENV-infected WT but no induction of these responses in SK1⁻/⁻ iMEFs. Reverse transciption PCR demonstrated a low-level induction of IFN-β and poor induction of mRNA for the interferon-stimulated genes (ISGs) viperin, IFIT1 and CXCL10 in DENV-infected SK1⁻/⁻ compared with WT iMEFs. Similarly, reduced induction of ISGs was observed in SK1⁻/⁻ 1°MEFs, even in the face of high-level DENV replication. In both iMEFs and 1°MEFs, DENV infection induced production of IFN-β protein. Additionally, higher basal levels of antiviral factors (IRF7, CXCL10 and OAS1) were observed in uninfected SK1⁻/⁻ iMEFs but not 1°MEFs. This suggests that, in this single iMEF line, lack of SK1 upregulates the basal levels of factors that may protect cells against DENV infection. More importantly, regardless of the levels of DENV replication, all cells that lacked SK1 produced IFN-β but were refractory to induction of ISGs such as viperin, IFIT1 and CXCL10. Based on these findings, we propose new roles for SK1 in affecting innate responses that regulate susceptibility to DENV infection.
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Affiliation(s)
- Jennifer N Clarke
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia
| | - Lorena K Davies
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia
| | - Julie K Calvert
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia
| | - Briony L Gliddon
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia
| | - Wisam H Al Shujari
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia
| | - Amanda L Aloia
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia
| | - Karla J Helbig
- School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Michael R Beard
- School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia
| | - Jillian M Carr
- Microbiology and Infectious Diseases, School of Medicine, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia
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29
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Sphingosine kinase 2 is a chikungunya virus host factor co-localized with the viral replication complex. Emerg Microbes Infect 2015; 4:e61. [PMID: 26576339 PMCID: PMC4631929 DOI: 10.1038/emi.2015.61] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 07/14/2015] [Accepted: 07/27/2015] [Indexed: 02/04/2023]
Abstract
Chikungunya virus (CHIKV) is a re-emerging alphavirus which causes severe and prolonged arthralgic febrile illness. The recent global spread of the virus and lack of approved therapeutic options makes it imperative to gain greater insight into the molecular mechanisms underlying CHIKV pathogenesis, in particular host factors recruited by the virus. In the current study, we identify sphingosine kinase 2 (SK2) as a CHIKV host factor co-localized with the viral replication complex (VRC) during infection. SK2 was demonstrated to co-localize with viral RNA and nonstructural proteins. Targeted impairment of SK2 expression or function significantly inhibited CHIKV infection. Furthermore, affinity purification-mass spectrometry studies revealed that SK2 associates with a number of proteins involved in cellular gene expression specifically during viral infection, suggesting a role in replication. Collectively these results identify SK2 as a novel CHIKV host factor.
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30
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Michels M, Japtok L, Alisjahbana B, Wisaksana R, Sumardi U, Puspita M, Kleuser B, de Mast Q, van der Ven AJAM. Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage. J Infect 2015; 71:480-7. [PMID: 26183296 DOI: 10.1016/j.jinf.2015.06.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/13/2015] [Accepted: 06/22/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND A transient endothelial hyperpermeability is a hallmark of severe dengue infections. Sphingosine-1-phosphate (S1P) maintains vascular integrity and protects against plasma leakage. We related plasma S1P levels to dengue-induced plasma leakage and studied mechanisms that may underlie the decrease in S1P levels in dengue. METHODS We determined circulating levels of S1P in 44 Indonesian adults with acute dengue and related levels to plasma leakage, as determined by daily ultrasonography, and to levels of its chaperone apolipoprotein M, other lipoproteins and platelets. RESULTS Plasma S1P levels were decreased during dengue and patients with plasma leakage had lower median levels compared to those without (638 vs. 745 nM; p < 0.01). ApoM and other lipoprotein levels were also decreased during dengue, but did not correlate to S1P levels. Platelet counts correlated positively with S1P levels, but S1P levels were not higher in frozen-thawed platelet rich plasma, arguing against platelets as an important cellular source of S1P in dengue. CONCLUSIONS Decreased plasma S1P levels during dengue are associated with plasma leakage. We speculate that decreased levels of ApoM underlies the lower S1P levels. Modulation of S1P levels and its receptors may be a novel therapeutic intervention to prevent plasma leakage in dengue.
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Affiliation(s)
- Meta Michels
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Lukasz Japtok
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Bachti Alisjahbana
- Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Rudi Wisaksana
- Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Uun Sumardi
- Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Mita Puspita
- Department of Internal Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Burkhard Kleuser
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam, Germany
| | - Quirijn de Mast
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Andre J A M van der Ven
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
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31
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Egom EE. Sphingosine-1-phosphate signalling as a therapeutic target for patients with abnormal glucose metabolism and ischaemic heart disease. J Cardiovasc Med (Hagerstown) 2015; 15:517-24. [PMID: 23839592 DOI: 10.2459/jcm.0b013e3283639755] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abnormalities of glucose metabolism in patients with ischaemic heart disease (IHD) are common and are associated with a poor outcome in patients with and without diabetes. Sphingosine-1-phosphate (S1P) is a bioactive lipid which has been shown to increase insulin sensitivity in rodents and to increase myocardial tolerance to ischaemia. In the present review, I explore the relevance of S1P signalling pathway to IHD and abnormalities in glucose tolerance, and its potential as a therapeutic target for patients with abnormal glucose metabolism and IHD.
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Affiliation(s)
- Emmanuel E Egom
- Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
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32
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Resop RS, Uittenbogaart CH. Human T-Cell Development and Thymic Egress: An Infectious Disease Perspective. FORUM ON IMMUNOPATHOLOGICAL DISEASES AND THERAPEUTICS 2015; 6:33-49. [PMID: 28670486 PMCID: PMC5489135 DOI: 10.1615/forumimmundisther.2015014226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emigration of mature naïve CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naïve T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases. To perform this work, we use a variety of humanized murine models reviewed in this article. Future work in the field of T-cell egress, especially as it pertains to S1P receptors, should advance the fields of basic T-cell immunology and immunopathology and open new avenues for exploration into novel therapeutics.
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Affiliation(s)
- Rachel S. Resop
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen Medical School at UCLA, Los Angeles, CA 90095
- Department of Pediatrics, David Geffen Medical School at UCLA, Los Angeles, CA 90095
| | - Christel H. Uittenbogaart
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen Medical School at UCLA, Los Angeles, CA 90095
- Department of Pediatrics, David Geffen Medical School at UCLA, Los Angeles, CA 90095
- University of California at Los Angeles AIDS Institute, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, David Geffen Medical School at UCLA, Los Angeles, CA 90095
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33
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Münzer P, Schmid E, Walker B, Fotinos A, Chatterjee M, Rath D, Vogel S, Hoffmann SM, Metzger K, Seizer P, Geisler T, Gawaz M, Borst O, Lang F. Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation. Am J Physiol Cell Physiol 2014; 307:C920-7. [PMID: 25231106 DOI: 10.1152/ajpcell.00029.2014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.
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Affiliation(s)
- Patrick Münzer
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Evi Schmid
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Britta Walker
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Anna Fotinos
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Madhumita Chatterjee
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Dominik Rath
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Sebastian Vogel
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Sascha M Hoffmann
- Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany
| | - Katja Metzger
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Peter Seizer
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Tobias Geisler
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Meinrad Gawaz
- Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Oliver Borst
- Department of Physiology, University of Tübingen, Tübingen, Germany. Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and
| | - Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany.
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34
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Potì F, Simoni M, Nofer JR. Atheroprotective role of high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P). Cardiovasc Res 2014; 103:395-404. [PMID: 24891400 DOI: 10.1093/cvr/cvu136] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Numerous epidemiological studies documented an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the extent of atherosclerotic disease. However, clinical interventions targeting HDL cholesterol failed to show clinical benefits with respect to cardiovascular risk reduction, suggesting that HDL components distinct from cholesterol may account for anti-atherogenic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P)-a lysosphingolipid exerting its biological activity via binding to specific G protein-coupled receptors and regulating a wide array of biological responses in a variety of different organs and tissues including the cardiovascular system-has been identified as an integral constituent of HDL particles. In the present review, we discuss current evidence from epidemiological studies, experimental approaches in vitro, and animal models of atherosclerosis, suggesting that S1P contributes to atheroprotective effects exerted by HDL particles.
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Affiliation(s)
- Francesco Potì
- Department of Biomedical, Metabolic and Neural Sciences-Endocrinology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Manuela Simoni
- Department of Biomedical, Metabolic and Neural Sciences-Endocrinology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Jerzy-Roch Nofer
- Department of Biomedical, Metabolic and Neural Sciences-Endocrinology Section, University of Modena and Reggio Emilia, Modena, Italy Center for Laboratory Medicine, University Hospital Münster, Albert-Schweizer-Campus 1, Geb. A1, Münster D-48149, Germany
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35
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Kroeker AL, Coombs KM. Systems biology unravels interferon responses to respiratory virus infections. World J Biol Chem 2014; 5:12-25. [PMID: 24600511 PMCID: PMC3942539 DOI: 10.4331/wjbc.v5.i1.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/11/2013] [Accepted: 01/06/2014] [Indexed: 02/05/2023] Open
Abstract
Interferon production is an important defence against viral replication and its activation is an attractive therapeutic target. However, it has long been known that viruses perpetually evolve a multitude of strategies to evade these host immune responses. In recent years there has been an explosion of information on virus-induced alterations of the host immune response that have resulted from data-rich omics technologies. Unravelling how these systems interact and determining the overall outcome of the host response to viral infection will play an important role in future treatment and vaccine development. In this review we focus primarily on the interferon pathway and its regulation as well as mechanisms by which respiratory RNA viruses interfere with its signalling capacity.
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36
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Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection. PLoS One 2013; 8:e75005. [PMID: 24137500 PMCID: PMC3796690 DOI: 10.1371/journal.pone.0075005] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 08/07/2013] [Indexed: 01/07/2023] Open
Abstract
Influenza continues to pose a threat to humans by causing significant morbidity and mortality. Thus, it is imperative to investigate mechanisms by which influenza virus manipulates the function of host factors and cellular signal pathways. In this study, we demonstrate that influenza virus increases the expression and activation of sphingosine kinase (SK) 1, which in turn regulates diverse cellular signaling pathways. Inhibition of SK suppressed virus-induced NF-κB activation and markedly reduced the synthesis of viral RNAs and proteins. Further, SK blockade interfered with activation of Ran-binding protein 3 (RanBP3), a cofactor of chromosome region maintenance 1 (CRM1), to inhibit CRM1-mediated nuclear export of the influenza viral ribonucleoprotein complex. In support of this observation, SK inhibition altered the phosphorylation of ERK, p90RSK, and AKT, which is the upstream signal of RanBP3/CRM1 activation. Collectively, these results indicate that SK is a key pro-viral factor regulating multiple cellular signal pathways triggered by influenza virus infection.
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37
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Carr JM, Kua T, Clarke JN, Calvert JK, Zebol JR, Beard MR, Pitson SM. Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3' untranslated region of dengue virus type-2 RNA. J Gen Virol 2013; 94:2437-2448. [PMID: 23939980 DOI: 10.1099/vir.0.055616-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) is a lipid kinase with important roles including regulation of cell survival. We have previously shown reduced SphK1 activity in cells with an established dengue virus type-2 (DENV-2) infection. In this study, we examined the effect of alterations in SphK1 activity on DENV-2 replication and cell death and determined the mechanisms of the reduction in SphK1 activity. Chemical inhibition or overexpression of SphK1 after established DENV-2 infection had no effect on infectious DENV-2 production, although inhibition of SphK1 resulted in enhanced DENV-2-induced cell death. Reduced SphK1 activity was observed in multiple cell types, regardless of the ability of DENV-2 infection to be cytopathic, and was mediated by a post-translational mechanism. Unlike bovine viral diarrhea virus, where SphK1 activity is decreased by the NS3 protein, SphK1 activity was not affected by DENV-2 NS3 but, instead, was reduced by expression of the terminal 396 bases of the 3' UTR of DENV-2 RNA. We have previously shown that eukaryotic elongation factor 1A (eEF1A) is a direct activator of SphK1 and here DENV-2 RNA co-localized and co-precipitated with eEF1A from infected cells. We propose that the reduction in SphK1 activity late in DENV-2-infected cells is a consequence of DENV-2 out-competing SphK1 for eEF1A binding and hijacking cellular eEF1A for its own replication strategy, rather than a specific host or virus-induced change in SphK1 to modulate viral replication. Nonetheless, reduced SphK1 activity may have important consequences for survival or death of the infected cell.
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Affiliation(s)
- J M Carr
- Flinders Medical Science and Technology, School of Medicine, Flinders University, University Drive, Bedford Park, Adelaide, South Australia 5042, Australia
| | - T Kua
- School of Molecular and Biomedical Science, University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia
| | - J N Clarke
- Flinders Medical Science and Technology, School of Medicine, Flinders University, University Drive, Bedford Park, Adelaide, South Australia 5042, Australia
| | - J K Calvert
- Flinders Medical Science and Technology, School of Medicine, Flinders University, University Drive, Bedford Park, Adelaide, South Australia 5042, Australia
| | - J R Zebol
- Centre for Cancer Biology, S.A. Pathology, Frome Rd, Adelaide, South Australia 5000, Australia
| | - M R Beard
- Centre for Cancer Biology, S.A. Pathology, Frome Rd, Adelaide, South Australia 5000, Australia
- School of Molecular and Biomedical Science, University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia
| | - S M Pitson
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia 5001, Australia
- Centre for Cancer Biology, S.A. Pathology, Frome Rd, Adelaide, South Australia 5000, Australia
- School of Molecular and Biomedical Science, University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia
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38
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Egom EE, Mamas MA, Soran H. HDL quality or cholesterol cargo: what really matters--spotlight on sphingosine-1-phosphate-rich HDL. Curr Opin Lipidol 2013; 24:351-6. [PMID: 23652570 DOI: 10.1097/mol.0b013e328361f822] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to their antiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-bound sphingosine-1-phosphate (S1P) plays a role in different HDL atheroprotective properties and may represent a potential target for therapeutic interventions. RECENT FINDINGS Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that many of the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable to its S1P cargo. HDL-associated S1P may represent a future therapeutic target. SUMMARY HDL functionality is affected by its composition and there is evidence to suggest S1P plays a role in some of HDL's functions and atheroprotective properties.
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Affiliation(s)
- Emmanuel E Egom
- Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
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Thiberville SD, Moyen N, Dupuis-Maguiraga L, Nougairede A, Gould EA, Roques P, de Lamballerie X. Chikungunya fever: epidemiology, clinical syndrome, pathogenesis and therapy. Antiviral Res 2013; 99:345-70. [PMID: 23811281 PMCID: PMC7114207 DOI: 10.1016/j.antiviral.2013.06.009] [Citation(s) in RCA: 322] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Revised: 05/21/2013] [Accepted: 06/18/2013] [Indexed: 12/11/2022]
Abstract
Chikungunya fever is caused by a mosquito-borne alphavirus originating in East Africa. During the past 7 years, the disease has spread to islands of the Indian Ocean, Asia and Europe. Its spread has been facilitated by a mutation favouring replication in the mosquito Ae. albopictus. No vaccines or antiviral drugs are available to prevent or treat chikungunya fever. This paper provides an extensive review of the virus and disease, including Supplementary Tables. Chikungunya virus (CHIKV) is the aetiological agent of the mosquito-borne disease chikungunya fever, a debilitating arthritic disease that, during the past 7 years, has caused immeasurable morbidity and some mortality in humans, including newborn babies, following its emergence and dispersal out of Africa to the Indian Ocean islands and Asia. Since the first reports of its existence in Africa in the 1950s, more than 1500 scientific publications on the different aspects of the disease and its causative agent have been produced. Analysis of these publications shows that, following a number of studies in the 1960s and 1970s, and in the absence of autochthonous cases in developed countries, the interest of the scientific community remained low. However, in 2005 chikungunya fever unexpectedly re-emerged in the form of devastating epidemics in and around the Indian Ocean. These outbreaks were associated with mutations in the viral genome that facilitated the replication of the virus in Aedes albopictus mosquitoes. Since then, nearly 1000 publications on chikungunya fever have been referenced in the PubMed database. This article provides a comprehensive review of chikungunya fever and CHIKV, including clinical data, epidemiological reports, therapeutic aspects and data relating to animal models for in vivo laboratory studies. It includes Supplementary Tables of all WHO outbreak bulletins, ProMED Mail alerts, viral sequences available on GenBank, and PubMed reports of clinical cases and seroprevalence studies.
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Affiliation(s)
- Simon-Djamel Thiberville
- UMR_D 190 "Emergence des Pathologies Virales" (Aix-Marseille Univ. IRD French Institute of Research for Development EHESP French School of Public Health), Marseille, France; University Hospital Institute for Infectious Disease and Tropical Medicine, Marseille, France.
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Post-translational regulation of sphingosine kinases. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:147-56. [DOI: 10.1016/j.bbalip.2012.07.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 07/04/2012] [Accepted: 07/06/2012] [Indexed: 12/22/2022]
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