Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice.

Ali A Almishaal,Matthew A Firpo,Anne Zhang,Jun Yang,Pranav D Mathur,Wayne M Yokoyama,Albert H Park,Liting Chen,Yong Wang,Elaine Hillas

doi:10.1371/journal.ppat.1006599

Abstract

Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.

Highlights

Cytomegalovirus (CMV) is the most common infectious cause of congenital sensorineural hearing loss (SNHL) in humans [1] with between 15–30% of pediatric hearing loss attributable to this infection [2,3,4]
We determined that Natural Killer (NK) cells interact with CMV infected cells through binding of the NK cell receptor, Ly49H, with a virally-encoded protein, m157, expressed on the cell surface of CMV infected inner ear cells, to mediate the protective effect
C57BL/6 mice are protected from murine CMV (mCMV)-induced hearing loss compared to BALB/c mice

Summary

Introduction

Cytomegalovirus (CMV) is the most common infectious cause of congenital sensorineural hearing loss (SNHL) in humans [1] with between 15–30% of pediatric hearing loss attributable to this infection [2,3,4]. Our group and others have successfully demonstrated that murine CMV (mCMV)-induced labyrinthitis in BALB/c murine newborn pups occurs when green fluorescent protein (GFP) expressing mCMV was used to inoculate newborn mice via an intracerebral (IC) injection [10, 11]. These studies recapitulate viral mediated hearing loss in human infant because a critical factor for effective correlation between the mouse model and the clinical condition is that the mouse auditory system at birth is analogous to the human fetal auditory system and does not achieve stable thresholds until 4 weeks of age [12]. Pass et al demonstrated an age dependent effect in children with congenital CMV infection who were more likely to develop hearing loss when infected during the first trimester rather than later in pregnancy [16]

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