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Influence of sphingosine-1-phosphate signaling on HCMV replication in human embryonal lung fibroblasts

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Abstract

The human cytomegalovirus (HCMV) is a common pathogen, which causes severe or even deadly diseases in immunocompromised patients. In addition, congenital HCMV infection represents a major health concern affecting especially the lung tissue of the susceptible individuals. Antivirals are a useful strategy to treat HCMV-caused diseases. However, all approved drugs target viral proteins but significant toxicity and an increasing resistance against these compounds have been observed. In infected cells, numerous host molecules have been identified to play important roles during HCMV replication. Among others, HCMV infection depends on the presence of bioactive sphingolipids. In this study, the role of sphingosine-1-phosphate (S1P) signaling in HCMV-infected human embryonal lung fibroblasts (HELF) was analyzed. Viral replication depended on the functional activity of sphingosine kinases (SK). During SK inhibition, addition of extracellular S1P restored HCMV replication. Moreover, neutralization of extracellular S1P by anti-S1P antibodies decreased HCMV replication as well. While the application of FTY720 as an functional antagonist of S1P receptor (S1PR)1,3−5 signaling did not reduce HCMV replication significantly, JTE-013, an inhibitor of S1PR2, decreased viral replication. Furthermore, inhibition of Rac-1 activity reduced HCMV replication, whereas inhibition of the Rac-1 effector protein Rac-1-activated kinase 1 (PAK1) had no influence. In general, targeting S1P-induced pathways, which are essential for a successful HCMV replication, may represent a valuable strategy to develop new antiviral drugs.

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Acknowledgements

We would like to thank Roger Sabbadini for providing the S1P-specific antibody Lpath Lt1002 as well as the non-specific control antibody Lpath Lt1013. We also thank Christian Sinzger (Institute of Virology, University of Ulm, Ulm, Germany) and Richard J. Stanton (Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK) for providing HCMV strains TB40/E and Merlin, respectively.

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  1. Anika Zilch and Christian Rien equally contributed.

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  1. Section Experimental Virology, Institute of Medical Microbiology, University Hospital Jena, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745, Jena, Germany

    Anika Zilch, Christian Rien, Stefanie Huskobla, Brigitte Glück, Andreas Sauerbrei & Andreas Henke

  2. Department for Molecular Cell Biology, Center for Molecular Biomedicine (CMB), University Hospital Jena, 07745, Jena, Germany

    Katrin Spengler & Regine Heller

  3. Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC) and the Center for Molecular Biomedicine (CMB), University Hospital Jena, 07745, Jena, Germany

    Cynthia Weigel & Markus Gräler

  4. Fritz Lipmann Institute, Leibniz Institute of Aging, 07745, Jena, Germany

    Cynthia Weigel

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Zilch, A., Rien, C., Weigel, C. et al. Influence of sphingosine-1-phosphate signaling on HCMV replication in human embryonal lung fibroblasts. Med Microbiol Immunol 207, 227–242 (2018). https://doi.org/10.1007/s00430-018-0543-4

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