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

Yushi Hayashi,Satoshi Koike,Takashi Fujita,Yasushi Kawaguchi,Naoto Koyanagi,Ikuno Uehara,Hidenori Suzuki,Toshiki Himeda,Shin-Ichiro Kitajiri,Atsuko Tanimura,Hiroki Kato,Tatsuya Katsuno,Wataru Nakajima,Mitsutoshi Yoneyama,Koji Onomoto,Nobuyuki Tanaka,Alan G Cheng

doi:10.1371/journal.pone.0260443

Abstract

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.

Highlights

The World Health Organization (WHO) has reported that 360 million people, more than 5% of the world’s population, suffer from disabling hearing loss [1]
We observed that Theiler’s murine encephalomyelitis virus (TMEV) infection is mainly established in supporting cells (SCs) and hair cells (HCs) infection is rarely observed in the presence of IFN-α/β produced by SCs that function as macrophage-like cells [12]
The time of infection establishment was different between SCs and GERCs, there were no significant differences between loss of inner HCs (IHCs) and outer HCs (OHCs) (Fig 1E)

Summary

Introduction

The World Health Organization (WHO) has reported that 360 million people, more than 5% of the world’s population, suffer from disabling hearing loss [1]. Hearing loss is classified into two types; namely, conductive hearing loss and sensorineural hearing loss (SHL), the latter of which is the main type of hearing disability [2]. SHL is mainly caused by damage to cochlear hair cells (HCs), which function as audiosensory receptors [3]. The aetiology of SHL has not been identified, it has been suggested that viral infections such as cytomegalovirus (CMV), rubella, mumps, measles and herpes simplex virus (HSV) can cause it, especially with sudden SHL (SSHL), which usually develops in one ear within 72 h of infection [4,5]. Systemic corticosteroid administration is the primary treatment of choice for SSHL [6]. Because very little is known about the mechanisms underlying this disease and the anti-infection protection system in the inner ear, corticosteroids are still used despite their limited efficacies

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Conclusion