Murine CMV-Induced Hearing Loss Is Associated with Inner Ear Inflammation and Loss of Spiral Ganglia Neurons

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Congenital infection with human cytomegalovirus (HCMV) is the most common viral infection of the fetus and occurs in 0.5–2.0% of all live births in most regions in the world. Infection of the fetus can result in a spectrum of end-organ disease, including long term damage to the central nervous system (CNS). Although less than 10% of infected infants exhibit clinical evidence of end-organ disease, up to 10% of the total number of infected infants develop hearing loss. Mechanisms of disease leading to hearing loss are poorly understood because of the limited availability of pathological specimens and accessibility of the inner ear. Existing small animal models fail to recapitulate many features of this infection of the inner ear. In this report we describe a mouse model in which newborn animals infected peripherally with murine CMV develop hearing loss following hematogenous spread of virus to the inner ear. Hearing loss occurs in 30–50% of animals and characteristics of hearing loss in infants with congenital HCMV infection, including delayed onset of hearing loss, progressive hearing loss, and unilateral hearing loss were present in infected mice. Our findings suggest that host derived inflammatory responses and not direct virus-mediated cytopathology are responsible for hearing loss. Findings from this study provide insight into potential mechanisms of hearing loss in infants with congenital HCMV infection.

Vyšlo v časopise: Murine CMV-Induced Hearing Loss Is Associated with Inner Ear Inflammation and Loss of Spiral Ganglia Neurons. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004774
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004774

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Zdroje

1. Boppana S, Britt WJ (2013) Synopsis of clinical aspects of human cytomegalovirus disease. In: Reddehasse M, editor. Cytomegaloviruses. London: Cassister.

2. Mocarski ES, Tan Courcelle C. (2001) Cytomegaloviruses and their replication. In: Howley DMKaPM, editor. Fields Virology. 4th ed. Philadelphia: Lippincott Williams and Wilkins. pp. 2629–2673.

3. Dreher AM, Arora N, Fowler KB, Novak Z, Britt WJ, et al. (2014) Spectrum of Disease and Outcome in Children with Symptomatic Congenital Cytomegalovirus Infection. J Pediatr 164 : 855–859. doi: 10.1016/j.jpeds.2013.12.007 24433826

4. Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, et al. (2000) Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. Journal of the American Academy of Audiology 11 : 283–290. 10821506

5. Fowler KB (2013) Congenital cytomegalovirus infection: audiologic outcome. Clin Infect Dis 57 Suppl 4: S182–184. doi: 10.1093/cid/cit609 24257423

6. Morton CC, Nance WE (2006) Newborn hearing screening—a silent revolution. N Engl J Med 354 : 2151–2164. 16707752

7. Yamamoto AY, Mussi-Pinhata MM, Isaac MDL, Amaral FR, Carvalheiro CG, et al. (2011) Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly seropositive population. Ped Infect Dis J 30 : 1043–1046. doi: 10.1097/INF.0b013e31822d9640 21814153

8. Dar L, Pati SK, Patro AR, Deorari AK, Rai S, et al. (2008) Congenital cytomegalovirus infection in a highly seropositive semi-urban population in India. Pediatr Infect Dis J 27 : 841–843. doi: 10.1097/INF.0b013e3181723d55 18645544

9. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK (2013) The "silent" global burden of congenital cytomegalovirus. Clin Microbiol Rev 26 : 86–102. doi: 10.1128/CMR.00062-12 23297260

10. Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, et al. (2003) Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial.[see comment]. Journal of Pediatrics 143 : 16–25. 12915819

11. Boppana SB, Britt WJ (2014) Recent approaches and strategies in the generation of antihuman cytomegalovirus vaccines. Methods Mol Biol 1119 : 311–348. doi: 10.1007/978-1-62703-788-4_17 24639230

12. Fowler KB, McCollister FP, Dahle AJ, Boppana S, Britt WJ, et al. (1997) Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. Journal of Pediatrics 130 : 624–630. 9108862

13. Davis LE, Johnsson LG, Kornfeld M (1981) Cytomegalovirus labyrinthitis in an infant: morphological, virological, and immunofluorescent studies. J Neuropathol Exp Neurol 40 : 9–19. 6259297

14. Boppana S, Britt W (2006) Cytomegalovirus. In: Newton VE, Vallely PJ, editors. Infection and Hearing Impairment. Sussex, UK: John Wiley and Sons. pp. 67–93.

15. Harris JP, Fan JT, Keithley EM (1990) Immunologic responses in experimental cytomegalovirus labyrinthitis. Am J Otolaryngol 11 : 304–308. 2176064

16. Woolf NK, Koehrn FJ, Harris JP, Richman DD (1989) Congenital cytomegalovirus labyrinthitis and sensorineural hearing loss in guinea pigs. J Infect Dis 160 : 929–937. 2555420

17. Park AH, Gifford T, Schleiss MR, Dahlstrom L, Chase S, et al. (2010) Development of cytomegalovirus-mediated sensorineural hearing loss in a Guinea pig model. Arch Otolaryngol Head Neck Surg 136 : 48–53. doi: 10.1001/archoto.2009.210 20083778

18. Wang Y, Patel R, Ren C, Taggart MG, Firpo MA, et al. (2013) A comparison of different murine models for cytomegalovirus-induced sensorineural hearing loss. Laryngoscope 123 : 2801–2806. doi: 10.1002/lary.24090 23616191

19. Schachtele SJ, Mutnal MB, Schleiss MR, Lokensgard JR Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 17 : 201–211. doi: 10.1007/s13365-011-0024-7 21416394

20. Juanjuan C, Yan F, Li C, Haizhi L, Ling W, et al. (2011) Murine model for congenital CMV infection and hearing impairment. Virol J 8 : 70. doi: 10.1186/1743-422X-8-70 21320351

21. Li L, Kosugi I, Han GP, Kawasaki H, Arai Y, et al. (2008) Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection. Lab Invest.

22. Katano H, Sato Y, Tsutsui Y, Sata T, Maeda A, et al. (2007) Pathogenesis of cytomegalovirus-associated labyrinthitis in a guinea pig model. Microbes Infect 9 : 183–191. 17208485

23. Koontz T, Bralic M, Tomac J, Pernjak-Pugel E, Bantug G, et al. (2008) Altered development of the brain after focal herpesvirus infection of the central nervous system. J Exp Med 205 : 423–435. doi: 10.1084/jem.20071489 18268036

24. Kosmac K, Bantug GR, Pugel EP, Cekinovic D, Jonjic S, et al. (2013) Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development. PLoS Pathog 9: e1003200. doi: 10.1371/journal.ppat.1003200 23505367

25. Jordan S, Krause J, Prager A, Mitrovic M, Jonjic S, et al. (2011) Virus progeny of murine cytomegalovirus bacterial artificial chromosome pSM3fr show reduced growth in salivary Glands due to a fixed mutation of MCK-2. J Virol 85 : 10346–10353. doi: 10.1128/JVI.00545-11 21813614

26. Zheng QY, Johnson KR, Erway LC (1999) Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 130 : 94–107. 10320101

27. Willott JF, Turner JG, Carlson S, Ding D, Seegers Bross L, et al. (1998) The BALB/c mouse as an animal model for progressive sensorineural hearing loss. Hear Res 115 : 162–174. 9472745

28. Brandt CT, Caye-Thomasen P, Lund SP, Worsoe L, Ostergaard C, et al. (2006) Hearing loss and cochlear damage in experimental pneumococcal meningitis, with special reference to the role of neutrophil granulocytes. Neurobiol Dis 23 : 300–311. 16798006

29. Klein M, Koedel U, Pfister HW, Kastenbauer S (2003) Morphological correlates of acute and permanent hearing loss during experimental pneumococcal meningitis. Brain Pathol 13 : 123–132. 12744466

30. Nadol JB Jr., Hsu WC (1991) Histopathologic correlation of spiral ganglion cell count and new bone formation in the cochlea following meningogenic labyrinthitis and deafness. Ann Otol Rhinol Laryngol 100 : 712–716. 1952661

31. Boppana SB, Britt WJ (2006) Cytomegalovirus. In: Newton VE, Vallely PJ, editors. Infection and Hearing Impairment. West Sussex, England: Wiley. pp. 67–91.

32. Teissier N, Delezoide AL, Mas AE, Khung-Savatovsky S, Bessieres B, et al. (2011) Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol 122 : 763–774. doi: 10.1007/s00401-011-0895-y 22033878

33. Schleiss MR (2006) Nonprimate models of congenital cytomegalovirus (CMV) infection: gaining insight into pathogenesis and prevention of disease in newborns. ILAR J 47 : 65–72. 16391432

34. Alam SA, Robinson BK, Huang J, Green SH (2007) Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells. J Comp Neurol 503 : 832–852. 17570507

35. Trune DR (1982) Influence of neonatal cochlear removal on the development of mouse cochlear nucleus: I. Number, size, and density of its neurons. J Comp Neurol 209 : 409–424. 7130465

36. Webster DB (1983) A critical period during postnatal auditory development of mice. Int J Pediatr Otorhinolaryngol 6 : 107–118. 6662618

37. Harris JA, Rubel EW (2006) Afferent regulation of neuron number in the cochlear nucleus: cellular and molecular analyses of a critical period. Hear Res 216–217 : 127–137.

38. Rubel EW, Fritzsch B (2002) Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci 25 : 51–101. 12052904

39. Tierney TS, Russell FA, Moore DR (1997) Susceptibility of developing cochlear nucleus neurons to deafferentation-induced death abruptly ends just before the onset of hearing. J Comp Neurol 378 : 295–306. 9120067

40. Harris JA, Iguchi F, Seidl AH, Lurie DI, Rubel EW (2008) Afferent deprivation elicits a transcriptional response associated with neuronal survival after a critical period in the mouse cochlear nucleus. J Neurosci 28 : 10990–11002. doi: 10.1523/JNEUROSCI.2697-08.2008 18945907

41. Mostafapour SP, Del Puerto NM, Rubel EW (2002) bcl-2 Overexpression eliminates deprivation-induced cell death of brainstem auditory neurons. J Neurosci 22 : 4670–4674. 12040073

42. Leake PA, Hradek GT, Hetherington AM, Stakhovskaya O (2011) Brain-derived neurotrophic factor promotes cochlear spiral ganglion cell survival and function in deafened, developing cats. J Comp Neurol 519 : 1526–1545. doi: 10.1002/cne.22582 21452221

43. Miller JM, Le Prell CG, Prieskorn DM, Wys NL, Altschuler RA (2007) Delayed neurotrophin treatment following deafness rescues spiral ganglion cells from death and promotes regrowth of auditory nerve peripheral processes: effects of brain-derived neurotrophic factor and fibroblast growth factor. J Neurosci Res 85 : 1959–1969. 17492794

44. Ramekers D, Versnel H, Grolman W, Klis SF (2012) Neurotrophins and their role in the cochlea. Hear Res 288 : 19–33. doi: 10.1016/j.heares.2012.03.002 22465680

45. Zhai SQ, Guo W, Hu YY, Yu N, Chen Q, et al. (2011) Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion. J Laryngol Otol 125 : 449–454. doi: 10.1017/S0022215110002112 21078216

46. Nickel R, Forge A (2008) Gap junctions and connexins in the inner ear: their roles in homeostasis and deafness. Curr Opin Otolaryngol Head Neck Surg 16 : 452–457. doi: 10.1097/MOO.0b013e32830e20b0 18797288

47. Ciuman RR (2009) Stria vascularis and vestibular dark cells: characterisation of main structures responsible for inner-ear homeostasis, and their pathophysiological relations. J Laryngol Otol 123 : 151–162. doi: 10.1017/S0022215108002624 18570690

48. Kennedy HJ (2012) New developments in understanding the mechanisms and function of spontaneous electrical activity in the developing mammalian auditory system. J Assoc Res Otolaryngol 13 : 437–445. doi: 10.1007/s10162-012-0325-4 22526733

49. Tritsch NX, Bergles DE (2010) Developmental regulation of spontaneous activity in the Mammalian cochlea. J Neurosci 30 : 1539–1550. doi: 10.1523/JNEUROSCI.3875-09.2010 20107081

50. Martin GK, Stagner BB, Lonsbury-Martin BL (2006) Assessment of cochlear function in mice: distortion-product otoacoustic emissions. Curr Protoc Neurosci Chapter 8: Unit8 21C.

51. Willott JF (2006) Measurement of the auditory brainstem response (ABR) to study auditory sensitivity in mice. Curr Protoc Neurosci Chapter 8: Unit8 21B.