Virus-infection in cochlear supporting cells induces audiosensory receptor hair cell death by TRAIL-induced necroptosis

PLoS One. 2021 Nov 29;16(11):e0260443. doi: 10.1371/journal.pone.0260443. eCollection 2021.


Although sensorineural hearing loss (SHL) is relatively common, its cause has not been identified in most cases. Previous studies have suggested that viral infection is a major cause of SHL, especially sudden SHL, but the system that protects against pathogens in the inner ear, which is isolated by the blood-labyrinthine barrier, remains poorly understood. We recently showed that, as audiosensory receptor cells, cochlear hair cells (HCs) are protected by surrounding accessory supporting cells (SCs) and greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) against viral infections. Here, we found that virus-infected SCs and GERCs induce HC death via production of the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Notably, the HCs expressed the TRAIL death receptors (DR) DR4 and DR5, and virus-induced HC death was suppressed by TRAIL-neutralizing antibodies. TRAIL-induced HC death was not caused by apoptosis, and was inhibited by necroptosis inhibitors. Moreover, corticosteroids, the only effective drug for SHL, inhibited the virus-induced transformation of SCs and GERCs into macrophage-like cells and HC death, while macrophage depletion also inhibited virus-induced HC death. These results reveal a novel mechanism underlying virus-induced HC death in the cochlear sensory epithelium and suggest a possible target for preventing virus-induced SHL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Hair Cells, Auditory / immunology
  • Hair Cells, Auditory / pathology
  • Hair Cells, Auditory / virology*
  • Hearing Loss, Sensorineural / immunology
  • Hearing Loss, Sensorineural / pathology
  • Hearing Loss, Sensorineural / virology*
  • Mice, Inbred ICR
  • Necroptosis*
  • TNF-Related Apoptosis-Inducing Ligand / immunology*
  • Virus Diseases / complications*
  • Virus Diseases / immunology
  • Virus Diseases / pathology


  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse

Grant support

This work was also supported by Japan Society for the Promotion of Science (JP) (a Grant-in-Aid for Young Scientists (B) (15K20240) and a Grant-in-Aid for Research Activity start-up (25893299)) to YH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.