Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model

  • Mattia Carraro
  • Ali Almishaal
  • Elaine Hillas
  • Matthew Firpo
  • Albert Park
  • Robert V. HarrisonEmail author
Research Article


Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.


congenital hearing loss sensorineural deafness corrosion casting scanning electron microscopy spiral limbus stria vascularis spiral ligament endocochlear potential endolymphatic potential 



This research was supported by a Canadian Institutes of Health Research (CIHR) grant (RVH) and a Triologic Career Development Award (AP). We thank Jaina Negandhi for her assistance in preparing the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Bego MG, Jeor SS (2006) Human cytomegalovirus infection of cells of hematopoietic origin: HCMV- induced immunosuppression, immune evasion, and latency. Exp Hematol 34:555–570CrossRefPubMedGoogle Scholar
  2. Bilavsky E, Shahar-Nissan K, Pardo J et al (2016) Hearing outcome of infants with congenital cytomegalovirus and hearing impairment. Arch Dis Child 101(5):433–438CrossRefPubMedGoogle Scholar
  3. Billett TE, Thorne PR, Gavin JB (1989) The nature and progression of injury in the organ of Corti during ischemia. Hear Res 41:189–197CrossRefPubMedGoogle Scholar
  4. Bradford RD, Yoo YG, Golemac M et al (2015) Murine CMV-induced hearing loss is associated with inner ear inflammation and loss of spiral ganglia neurons. PLoS Pathog 11(4):e1004774. doi: 10.1371/journal.ppat.1004774 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Carraro M, Harrison RV (2016) Degeneration of stria vascularis in age-related hearing loss; a corrosion cast study in a mouse model. Acta Otolaryngol 136(4):385–390CrossRefPubMedGoogle Scholar
  6. Carraro M, Park AH, Harrison RV (2016) Partial corrosion casting to assess cochlear vasculature in mouse models of presbycusis and CMV infection. Hear Res 332:95–103CrossRefPubMedGoogle Scholar
  7. Choi KY, Schimmenti LA, Jurek AM (2009) Detection of cytomegalovirus DNA in dried blood spots of Minnesota infants who do not pass newborn hearing screening. Pediatr Infect Dis J 28(12):1095–1098CrossRefPubMedGoogle Scholar
  8. Cohen-Salmon M, Regnault B, Cayet N et al (2007) Connexin 30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis. Proc Natl Acad Sci U S A 104:6229–6234CrossRefPubMedPubMedCentralGoogle Scholar
  9. Delany I, Rappuoli R, De Gregorio E (2014) Vaccines for the twenty-first century. EMBO Molecular Medicine 6(6):708–720PubMedPubMedCentralGoogle Scholar
  10. Demmler GJ (1991) Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease Rev Infect Dis 13:315–329PubMedGoogle Scholar
  11. Fowler KB, Boppana SB (2006) Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 35:226–231CrossRefPubMedGoogle Scholar
  12. Fowler KB, Dahle AJ, Boppana SB et al (1999) Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed? J. Pediatr 135(1):60–64CrossRefGoogle Scholar
  13. Fowler KB, McCollister FP, Dahle AJ et al (1997) Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr 130:624–630CrossRefPubMedGoogle Scholar
  14. Foulon I, Naessens A, Faron G et al (2012) Hearing thresholds in children with a congenital CMV infection: a prospective study. Int J Pediatr Otorhinolaryngol 76:712–717CrossRefPubMedGoogle Scholar
  15. Foulon I, Naessens A, Foulon W et al (2008) A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr 153:84–88CrossRefPubMedGoogle Scholar
  16. Gafni M, Sohmer H (1976) Intermediate endocochlear potential levels induced by hypoxia. Acta Otolaryngol 82:354–358CrossRefPubMedGoogle Scholar
  17. Goderis J, De Leenheer E, Smets K (2014) Hearing loss and congenital CMV infection: a systematic review. Pediatrics 134(5):972–982CrossRefPubMedGoogle Scholar
  18. Grosse SD, Ross DS, Dollard SC (2008) Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol 41:57–62CrossRefPubMedGoogle Scholar
  19. Hibino H, Nin F, Tsuzuki C et al (2010) How is the highly positive endocochlear potential formed? The specific architecture of the stria vascularis and the roles of the ion-transport apparatus. Pflugers Arch 459:521–533CrossRefPubMedGoogle Scholar
  20. Kasai M, Yoneda T, Habu S et al (1981) In vivo effect of anti-asialo GM1 antibody in natural killer activity. Nature 291(5813):334–335CrossRefPubMedGoogle Scholar
  21. Kimberlin DW, Jester PM, Sanchez PJ et al (2015) Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med 372:933–943CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kimberlin DW, Lin C, Sánchez PJ (2003) Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 143(1):16–25CrossRefPubMedGoogle Scholar
  23. Kus LH, Negandhi J, Sklar MC et al (2014) Angiogenesis in costal cartilage graft laryngotracheoplasty: a corrosion casting study in piglets. Laryngoscope 124(10):2411–2417CrossRefPubMedGoogle Scholar
  24. Lawrence M, Nuttali AL, Burgio PA (1975) Cochlear potentials and oxygen associated with hypoxia. Ann Otol Rhinol Laryngol 84:499–512CrossRefPubMedGoogle Scholar
  25. Li L, Kosugi L, Han GP et al (2008) Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection. Lab Investig 88:722–730CrossRefPubMedGoogle Scholar
  26. Li X, Shi X, Wang C et al (2015) Pathological changes of the inner ear cochlea in different time windows of murine cytomegalovirus-induced hearing loss in a mouse model. Acta Otolaryngol 135:536–541CrossRefPubMedGoogle Scholar
  27. Macchiarelli G, Jiang JY, Nottola SA et al (2006) Morphological patterns of angiogenesis in ovarian follicle capillary networks. A scanning electron microscopy study of corrosion cast Microsc Res Tech 69:459–468PubMedGoogle Scholar
  28. Manicklal S, Emery VC, Lazzarotto T et al (2013) The ‘silent’ global burden of congenital cytomegalovirus. Clin Microbiol Rev 26:86–102CrossRefPubMedPubMedCentralGoogle Scholar
  29. Misono S, Sie KC, Weiss NS et al (2011) Congenital cytomegalovirus infection in pediatric hearing loss. Arch Otolaryngol Head Neck Surg 137(1):47–53CrossRefPubMedPubMedCentralGoogle Scholar
  30. Neng L, Zhang F, Kachelmeier A et al (2013) Endothelial cell, pericyte, and perivascular resident macrophage—type melanocyte interactions regulate cochlear intrastrial fluid-blood barrier permeability. J Assoc Res Otolaryngol 14(2):175–185CrossRefPubMedGoogle Scholar
  31. Otis EM, Brent R (1954) Equivalent ages in mouse and human embryos. Anat Rec 120:33–63CrossRefPubMedGoogle Scholar
  32. Park AH, Duval M, McVicar S et al (2014) A diagnostic paradigm including cytomegalovirus testing for idiopathic pediatric sensorineural hearing loss. Laryngoscope 124:2624–2629CrossRefPubMedGoogle Scholar
  33. Pass RF, Fowler KB, Boppana SB et al (2006) Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol 35(2):216–220CrossRefPubMedGoogle Scholar
  34. Patuzzi R (2011) Ion flow in stria vascularis and the production and regulation of cochlear endolymph and the endolymphatic potential. Hear Res 277:4–19CrossRefPubMedGoogle Scholar
  35. Perlman HB, Kimura R, Fernandez C (1959) Experiments on temporary obstruction of the internal auditory artery. Laryngoscope 69(6):591–613CrossRefPubMedGoogle Scholar
  36. Royackers L, Christian D, Frans D et al (2011) Hearing status in children with congenital cytomegalovirus: up-to 6 years audiological follow-up. Int J Pediatr Otorhinolaryngol 75:376–382CrossRefPubMedGoogle Scholar
  37. Salt AN, Melichar I, Thalmann R (1987) Mechanisms of endocochlear potential generation by stria vascularis. Laryngoscope 97:984–991CrossRefPubMedGoogle Scholar
  38. Sawada S, Mori N, Mount RJ et al (2001) Differential vulnerability of inner and outer hair cell systems to chronic mild hypoxia and glutamate ototoxicity; insights into auditory neuropathy. J Otolaryngol 30:106–114CrossRefPubMedGoogle Scholar
  39. Schachtele SJ, Mutnal MB, Schleiss MR et al (2011) Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 17:201–211CrossRefPubMedPubMedCentralGoogle Scholar
  40. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Meth 9:671–675CrossRefGoogle Scholar
  41. Schulte BA, Schmiedt RA (1992) Lateral wall Na, K-ATPase and endocochlear potentials decline with age in quiet-reared gerbils. Hear Res 61:35–46CrossRefPubMedGoogle Scholar
  42. Sewell WF (1984) The effects of furosemide on the endocochlear potential and auditory-nerve fiber tuning curves in cats. Hear Res 14:305–314CrossRefPubMedGoogle Scholar
  43. Shi X (2010) Resident macrophages in the cochlear blood-labyrinth barrier and their renewal via migration of bone-marrow-derived cells. Cell Tissue Res 342:21–30CrossRefPubMedGoogle Scholar
  44. Söderberg-Nauclér C, Streblow DN, Fish KN (2001) Reactivation of latent human cytomegalovirus in CD14(+) monocytes is differentiation dependent. J Virol 75:7543–7554CrossRefPubMedPubMedCentralGoogle Scholar
  45. Sohmer H, Freeman S, Schmuel M (1989) ABR threshold is a function of blood oxygen level. Hear Res 40:87–91CrossRefPubMedGoogle Scholar
  46. Steel KP, Barkway C (1989) Another role for melanocytes: their importance for normal stria vascularis development in the mammalian inner ear. Development 107:453–463PubMedGoogle Scholar
  47. Tabuchi K, Ito Z, Wada T et al (1998) The effect of mannitol upon cochlear dysfunction induced by transient local anoxia. Hear Res 126:28–36CrossRefPubMedGoogle Scholar
  48. Thalmann R, Miyoshi T, Thalmann I (1972) The influence of ischemia upon the energy reserves of inner ear tissues. Laryngoscope 82:2249–2272CrossRefPubMedGoogle Scholar
  49. Wang Y, Patel R, Ren C et al (2013) A comparison of different murine models for cytomegalovirus-induced sensorineural hearing loss. Laryngoscope 123:2801–2806CrossRefPubMedGoogle Scholar

Copyright information

© Association for Research in Otolaryngology 2016

Authors and Affiliations

  • Mattia Carraro
    • 1
    • 2
  • Ali Almishaal
    • 3
  • Elaine Hillas
    • 4
  • Matthew Firpo
    • 4
  • Albert Park
    • 4
    • 5
  • Robert V. Harrison
    • 1
    • 2
    • 6
    Email author
  1. 1.Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoCanada
  2. 2.Auditory Science Laboratory, Neuroscience and Mental Health ProgramThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Communication Sciences and DisordersUniversity of UtahSalt Lake CityUSA
  4. 4.Department of SurgeryUniversity of UtahSalt Lake CityUSA
  5. 5.Department of OtolaryngologyUniversity of UtahSalt Lake CityUSA
  6. 6.Department of Otolaryngology, Head and Neck SurgeryUniversity of TorontoTorontoCanada

Personalised recommendations