Zika virus infection causes widespread damage to the inner ear

Abstract

Zika virus (ZIKV) has been recently recognized as a causative agent of newborn microcephaly, as well as other neurological consequences. A less well recognized comorbidity of prenatal ZIKV infection is hearing loss, but cases of hearing impairment following adult ZIKV infection have also been recognized. Diminished hearing following prenatal ZIKV infection in a mouse model has been reported, but no cellular consequences were observed. We examined the effects of ZIKV infection on inner ear cellular integrity and expression levels of various proteins important for cochlear function in type I interferon receptor null (Ifnar1 −/− ) mice following infection at 5-6 weeks of age. We show that ZIKV antigens are present in cells within the cochlear epithelium, lateral wall, spiral limbus and spiral ganglion. Here we show that ZIKV infection alters cochlear expression of genes that signal cell damage (S100B), transport fluids (AQP1), are gaseous transmitters (eNOs) and modulate immune response (F4/80). Morphological analyses shows that not only are cochlear structures compromised by ZIKV infection, but damage also occurs in vestibular end organs. ZIKV produces a graded distribution of cellular damage in the cochlea, with greatest damage in the apex similar to that reported for cytomegalovirus (CMV) infection. The graded distribution of damage may indicate a differential susceptibility to ZIKV along the cochlear tonotopic axis. Collectively, these data are the first to show the molecular and morphological damage to the inner ear induced by ZIKV infection in adults and suggests multiple mechanisms contributing to the hearing loss reported in the human population.

Embryonic and Neonatal Mouse Cochleae Are Susceptible to Zika Virus Infection

“…The susceptibility of the inner ear tissues to ZIKV was recently reported for two vertebrate animal models: chicken embryos [9] and adult mice with compromised immune systems [10]. In the chicken embryo, our group found that the inner ear could be infected by direct delivery of virus into the fluid compartment of the inner ear.…”

“…This suggests that the different inner ear cell types may have specific critical periods of susceptibility and sensitivity to ZIKV, although until now this has not been tested in an embryonic mammalian inner ear. In the 5−6-week-old immunocompromised mouse, systemic ZIKV delivery resulted in infection of the inner ears as well as subsequent histological pathologies at 9 days post-infection [10]. Cellular damage (swelling, intracellular vacuoles, translocation of the nucleus and/or apical surface blebbing) was observed in the sensory epithelia (both auditory and vestibular) or in the spiral ganglion, whose axons bundle to form the auditory nerve.…”

Congenital Deafness and Recent Advances Towards Restoring Hearing Loss

“…A bioinformatics and in vitro study showed the activation of a proliferative and pro-apoptotic P-53 related response in human neural progenitor cells in response to ZIKV ( Ghouzzi et al, 2016 ). Infection in adult mice revealed the presence of vacuolization in the stria vascularis, the dark cells of the vestibule, and the spiral ganglion ( Yee, Neupane, Bai, & Vetter, 2020 ). In utero infection of mice led to hearing deficits in 25% to 66% of the offspring, with a greater deficit at higher frequencies ( Julander et al, 2018 ).…”

Nanoparticles for the Treatment of Inner Ear Infections

“…A relation between Zika virus infection and hearing loss was also reported in both infants and adults. Zika virus was found to produce a graded distribution of cellular damage in the cochlea, with the greatest damage in the apex, in a manner similar to cytomegalovirus infection [ 32 , 40 , 41 ].…”