Embryonic and Neonatal Mouse Cochleae Are Susceptible to Zika Virus Infection.

Vidhya Munnamalai,Richard J Kuhn,Donna M Fekete,Ankita Thawani,Caryl A Young,Nabilah H Sammudin

doi:10.3390/v13091823

Vidhya Munnamalai, Richard J Kuhn + Show 4 more

Open Access

https://doi.org/10.3390/v13091823

Copy DOI

Abstract

Congenital Zika Syndrome (CZS) is caused by vertical transmission of Zika virus (ZIKV) to the gestating human fetus. A subset of CZS microcephalic infants present with reduced otoacoustic emissions; this test screens for hearing loss originating in the cochlea. This observation leads to the question of whether mammalian cochlear tissues are susceptible to infection by ZIKV during development. To address this question using a mouse model, the sensory cochlea was explanted at proliferative, newly post-mitotic or maturing stages. ZIKV was added for the first 24 h and organs cultured for up to 6 days to allow for cell differentiation. Results showed that ZIKV can robustly infect proliferating sensory progenitors, as well as post-mitotic hair cells and supporting cells. Virus neutralization using ZIKV-117 antibody blocked cochlear infection. AXL is a cell surface molecule known to enhance the attachment of flavivirus to host cells. While Axl mRNA is widely expressed in embryonic cochlear tissues susceptible to ZIKV infection, it is selectively downregulated in the post-mitotic sensory organ by E15.5, even though these cells remain infectible. These findings may offer insights into which target cells could potentially contribute to hearing loss resulting from fetal exposure to ZIKV in humans.

Highlights

Zika virus (ZIKV) is a flavivirus that received world-wide attention in 2015 when a Brazilian outbreak revealed that ZIKV infection of pregnant women was linked to severe birth defects in their newborns [1]
To determine that supporting cells were infected with ZIKV, we looked for clustered dsRNA-positive pixels within the supporting cell layer; this layer was marked by dense, small nuclei labeled with an anti-Sox2 antibody to the transcription factor SOX2
The mouse cochlea undergoes major morphogenetic and cellular changes that could affect its susceptibility to ZIKV as development progresses

Summary

Introduction

Zika virus (ZIKV) is a flavivirus that received world-wide attention in 2015 when a Brazilian outbreak revealed that ZIKV infection of pregnant women was linked to severe birth defects in their newborns [1]. Hearing loss was linked to in utero ZIKV exposure in 12% of 114 infants evaluated during the second year of life [3]. A review of 27 studies that looked for a positive correlation between fetal ZIKV exposure and congenital hearing loss shows a wide range in this co-morbidity [4]. Non-invasive screening for hearing loss in infants utilizes two methods that interrogate different parts of the auditory system (reviewed by [5,6,7]). Otoacoustic emission (OAE) can identify defects in the peripheral auditory system, in the outer hair cells of the organ of Corti (the sensory organ for hearing in a mammalian inner ear).

Methods

Results

Conclusion