Ali Almishaal1, Pranav Dinesh Mathur2, Lesley Franklin3, Kevin Shi4, Travis Haller4, Aleksandra Martinovic5, Kayla Hirschmugl6, Brian R Earl7, Chong Zhang8, Jun Yang9, Michael R Deans10, Matthew A Firpo11, Albert H Park12. 1. College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia. 2. Otonomy Inc, San Diego, CA, USA; Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA. 3. Department of Audiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 4. Division of Otolaryngology, University of Utah, UT, USA; Department of Surgery, University of Utah, UT, USA. 5. Department of Audiology, Mercy Children's Hospital, Kansas City, KS, USA. 6. Hearing and Speech Center, Children's National, Washington. D.C., USA. 7. Department of Communication Sciences and Disorders, University of Cincinnati, Cincinnati, OH, USA. 8. Department of Internal Medicine- Epidemiology, University of Utah, UT, USA. 9. Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA. 10. Department of Ophthalmology & Visual Sciences, University of Utah, Salt Lake City, UT, USA; Division of Otolaryngology, University of Utah, UT, USA; Department of Surgery, University of Utah, UT, USA. 11. Department of Surgery, University of Utah, UT, USA. 12. Division of Otolaryngology, University of Utah, UT, USA; Department of Surgery, University of Utah, UT, USA. Electronic address: albert.park@hsc.utah.edu.
Abstract
OBJECTIVES: Determine whether a murine model of cytomegalovirus (CMV) and CMV- infected children show evidence of synaptopathy. STUDY DESIGN: Murine model of CMV infection and case series. SUBJECTS AND METHODS: C57 BL/6 mice were inoculated with murine-CMV (mCMV). Auditory function was assessed using Auditory Brainstem Response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Temporal bones from mCMV-infected mice were used for both ribbon synapse and hair cell quantification. Four groups of children (non-CMV normal hearing, non-CMV hearing impaired, CMV normal hearing and CMV hearing impaired) underwent ABRs between 2014 and 2018. The outcomes included raw amplitude, wave I:V amplitude ratio, absolute latency, and interpeak latency. RESULTS: Mice at 8 weeks post mCMV infection had higher ABR and DPOAE (P < 0.05) thresholds and increased outer hair cell loss compared to uninfected mice and mCMV-infected mice at 4 and 6 weeks post infection, indicating progressive hearing loss. A reduction in the wave I amplitude and synaptic counts were noted earlier at 4 weeks in CMV-infected mice (P < 0.05). The human data indicated that the wave I:V amplitude ratio was lower on average in CMV-infected groups when compared to the uninfected cohorts. The wave I:V amplitude ratio for the click and 4k stimuli were not significantly different between the congenital CMV-infected and uninfected children with normal or with hearing loss. CONCLUSION: This study suggests mCMV infection results in a synaptopathy before hair cell damage. Additional studies need to be performed to determine whether this effect is also observed in CMV-infected children. LEVEL OF EVIDENCE: Animal studies and basic science- NA; human studies: level 4.
OBJECTIVES: Determine whether a murine model of cytomegalovirus (CMV) and CMV- infected children show evidence of synaptopathy. STUDY DESIGN: Murine model of CMV infection and case series. SUBJECTS AND METHODS: C57 BL/6 mice were inoculated with murine-CMV (mCMV). Auditory function was assessed using Auditory Brainstem Response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Temporal bones from mCMV-infected mice were used for both ribbon synapse and hair cell quantification. Four groups of children (non-CMV normal hearing, non-CMV hearing impaired, CMV normal hearing and CMV hearing impaired) underwent ABRs between 2014 and 2018. The outcomes included raw amplitude, wave I:V amplitude ratio, absolute latency, and interpeak latency. RESULTS: Mice at 8 weeks post mCMV infection had higher ABR and DPOAE (P < 0.05) thresholds and increased outer hair cell loss compared to uninfected mice and mCMV-infected mice at 4 and 6 weeks post infection, indicating progressive hearing loss. A reduction in the wave I amplitude and synaptic counts were noted earlier at 4 weeks in CMV-infected mice (P < 0.05). The human data indicated that the wave I:V amplitude ratio was lower on average in CMV-infected groups when compared to the uninfected cohorts. The wave I:V amplitude ratio for the click and 4k stimuli were not significantly different between the congenital CMV-infected and uninfected children with normal or with hearing loss. CONCLUSION: This study suggests mCMV infection results in a synaptopathy before hair cell damage. Additional studies need to be performed to determine whether this effect is also observed in CMV-infected children. LEVEL OF EVIDENCE: Animal studies and basic science- NA; human studies: level 4.
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