@phdthesis{Chithelen2022,
  author    = {Chithelen, Janice},
  title     = {Targeting viral and host factors to optimize anti-measles virus therapy},
  doi       = {10.25972/OPUS-29305},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293059},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Measles is an ancient disease with historical records as early as the 9th century. Extensive study as well as advances in scientific knowledge of virology have led to identification of the viral pathogen and subsequent development of an effective vaccine leading to global efforts towards measles elimination. In 2018, around 140,000 deaths were reported due to measles with incomplete vaccine coverage being one of the leading causes of resurgence. Measles is highly contagious and often regarded as a childhood illness. However, measles is associated with a number of complications and persistent infections like subacute sclerosing panencephalitis (SSPE), which have brought into focus the need for specific anti-viral therapies. The aim of this study was to target host and viral factors to optimize anti-measles virus therapy. Our approach was to test a panel of compounds known to inhibit host cell functions or viral factors for their antiviral effect on measles replication. Primary human lymphocytes, persistently infected NT2 cells and post-mitotic neurons were used as in vitro model systems of acute, persistent and neuronal infection respectively to test the inhibitors. Using the inhibitors Ceranib-2 and SKI-II to target the sphingolipid metabolism enzymes acid ceramidase and sphingosine kinase in infected human primary lymphocytes, we observed a decreased protein translational capacity mediated by mTORC1, EIF4E and ribosomal protein S6 phosphorylation that probably contributes to the antiviral effect. In the persistently infected neural NT2 cells and post-mitotic neurons derived from LUHMES cells, we observed effective infection inhibition and viral clearance upon treatment with a small non-nucleoside inhibitor (ERDRP-0519) specifically targeting the Morbillivirus large polymerase. Other inhibitors such as Ribavirin and Favipiravir were less effective. To conclude, 1) we identified a mTOR associated protein translation axis associated with the sphingolipid metabolism, which affects measles virus replication and 2) In vitro persistently infected neuronal and post-mitotic neuron models were successfully used as a rapid method to test antivirals against measles virus.},
  language  = {en}
}
@article{ChithelenFrankeLaenderetal.2022,
  author    = {Chithelen, Janice and Franke, Hannah and L{\"a}nder, Nora and Grafen, Anika and Schneider-Schaulies, J{\"u}rgen},
  title     = {The sphingolipid inhibitors ceranib-2 and SKI-II reduce measles virus replication in primary human lymphocytes: effects on mTORC1 downstream signaling},
  series = {Frontiers in Physiology},
  volume    = {13},
  journal   = {Frontiers in Physiology},
  issn      = {1664-042X},
  doi       = {10.3389/fphys.2022.856143},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265988},
  year      = {2022},
  abstract  = {The bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P) are involved in the regulation of cell homeostasis and activity ranging from apoptosis to proliferation. We recently described that the two compounds ceranib-2 (inhibiting acid ceramidase) and SKI-II [inhibiting the sphingosine kinases 1 and - 2 (SphK1/2)] reduce mTORC1 activity and measles virus (MV) replication in human primary peripheral blood lymphocytes (PBL) by about one log step. We now further investigated whether mTORC1 downstream signaling and viral protein expression may be affected by ceranib-2 and/or SKI-II. Western blot analyses showed that in uninfected cells the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) was reduced by both inhibitors. Interestingly, MV infection led to an increase of rpS6 protein levels and phosphorylation of eIF4E. Treatment with both inhibitors reduced the rpS6 protein expression, and in addition, SKI-II reduced rpS6 phosphorylation. The phosphorylation of eIF4E was slightly reduced by both inhibitors. In addition, SKI-II led to reduced levels of IKK in MV-infected cells. Both inhibitors reduced the expression of viral proteins and the titers of newly synthesized MV by approximately one log step. As expected, SKI-II and rapamycin reduced also the virally encoded GFP expression; however, ceranib-2 astonishingly led to increased levels of GFP fluorescence. Our findings suggest that the inhibitors ceranib-2 and SKI-II act via differential mechanisms on MV replication. The observed effects on mTORC1 downstream signaling, predominantly the reduction of rpS6 levels by both inhibitors, may affect the translational capacity of the cells and contribute to the antiviral effect in human primary PBL.},
  language  = {en}
}