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Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

Research output: Contribution to journalArticle

  • Carles Solà-Riera
  • Shawon Gupta
  • Kimia T Maleki
  • Patricia González-Rodriguez
  • Dalel Saidi
  • Christine L Zimmer
  • Sindhu Vangeti
  • Laura Rivino
  • Yee-Sin Leo
  • David Chien Lye
  • Paul A MacAry
  • Clas Ahlm
  • Anna Smed-Sörensen
  • Bertrand Joseph
  • Niklas K Björkström
  • Hans-Gustaf Ljunggren
  • Jonas Klingström
Original languageEnglish
Pages (from-to)2124-2139.e6
JournalCell Reports
Issue number8
DateAccepted/In press - 18 Jul 2019
DatePublished (current) - 20 Aug 2019


Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.

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Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.


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