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. 1997 Nov;65(11):4411–4418. doi: 10.1128/iai.65.11.4411-4418.1997

A role for pneumolysin but not neuraminidase in the hearing loss and cochlear damage induced by experimental pneumococcal meningitis in guinea pigs.

A J Winter 1, S D Comis 1, M P Osborne 1, M J Tarlow 1, J Stephen 1, P W Andrew 1, J Hill 1, T J Mitchell 1
PMCID: PMC175634  PMID: 9353013

Abstract

We investigated the roles of pneumolysin and neuraminidase in the pathogenesis of deafness and cochlear damage during experimental pneumococcal meningitis. Anesthetized guinea pigs were inoculated intracranially with 7.5 log10 CFU of either (i) wild-type Streptococcus pneumoniae D39 (n = 8), (ii) PLN-A, a defined isogenic derivative of D39 deficient in pneumolysin (n = 5), or (iii) deltaNA1, a new derivative of D39 deficient in neuraminidase constructed by insertion-duplication mutagenesis of the nanA gene (n = 5). To quantify hearing loss, the auditory nerve compound action potential evoked by a tone pulse was recorded from the round window membrane of the cochlea every 3 h for 12 h. The organ of Corti was intravitally fixed for subsequent examination by high-resolution scanning and transmission electron microscopy. All animals sustained similar meningeal inflammatory responses. PLN-A induced significantly less hearing loss than D39 over the frequency range of 3 to 10 kHz. Levels of mean hearing loss at 10 kHz 12 h postinoculation were as follows: D39, 50 dB; deltaNA1, 52 dB (P = 0.76 versus D39), and PLN-A, 12 dB (P < 0.0001 versus D39). The mean rates of hearing loss at 10 kHz were 4.4 dB/h for D39, 4.3 dB/h for deltaNA1, and just 1.0 dB/h for PLN-A (P < 0.0001 versus D39). Suppurative labyrinthitis was universal. PLN-A induced the accumulation of less protein in the cerebrospinal fluid (P = 0.04 versus D39). Infection with D39 and deltaNA1 induced significant damage to the reticular lamina, the sensory hair cells, and supporting cells of the organ of Corti. By contrast, after infection with PLN-A, the organ of Corti appeared virtually intact. Pneumolysin seems to be the principal cause of cochlear damage in this model of meningogenic deafness. No clear pathogenic role was demonstrated for neuraminidase.

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Selected References

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  1. Alwmark A., Bengmark S., Gullstrand P., Schalén C. Improvement of the splenectomized rat model for overwhelming pneumococcal infection. Standardization of the bacterial inocula. Eur Surg Res. 1981;13(5):339–343. doi: 10.1159/000128200. [DOI] [PubMed] [Google Scholar]
  2. Amaee F. R., Comis S. D., Osborne M. P. NG-methyl-L-arginine protects the guinea pig cochlea from the cytotoxic effects of pneumolysin. Acta Otolaryngol. 1995 May;115(3):386–391. doi: 10.3109/00016489509139334. [DOI] [PubMed] [Google Scholar]
  3. Benton K. A., Everson M. P., Briles D. E. A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. Infect Immun. 1995 Feb;63(2):448–455. doi: 10.1128/iai.63.2.448-455.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berry A. M., Lock R. A., Paton J. C. Cloning and characterization of nanB, a second Streptococcus pneumoniae neuraminidase gene, and purification of the NanB enzyme from recombinant Escherichia coli. J Bacteriol. 1996 Aug;178(16):4854–4860. doi: 10.1128/jb.178.16.4854-4860.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berry A. M., Yother J., Briles D. E., Hansman D., Paton J. C. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect Immun. 1989 Jul;57(7):2037–2042. doi: 10.1128/iai.57.7.2037-2042.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bhatt S. M., Cabellos C., Nadol J. B., Jr, Halpin C., Lauretano A., Xu W. Z., Tuomanen E. The impact of dexamethasone on hearing loss in experimental pneumococcal meningitis. Pediatr Infect Dis J. 1995 Feb;14(2):93–96. doi: 10.1097/00006454-199502000-00002. [DOI] [PubMed] [Google Scholar]
  7. Bhatt S. M., Lauretano A., Cabellos C., Halpin C., Levine R. A., Xu W. Z., Nadol J. B., Jr, Tuomanen E. Progression of hearing loss in experimental pneumococcal meningitis: correlation with cerebrospinal fluid cytochemistry. J Infect Dis. 1993 Mar;167(3):675–683. doi: 10.1093/infdis/167.3.675. [DOI] [PubMed] [Google Scholar]
  8. Bhatt S., Halpin C., Hsu W., Thedinger B. A., Levine R. A., Tuomanen E., Nadol J. B., Jr Hearing loss and pneumococcal meningitis: an animal model. Laryngoscope. 1991 Dec;101(12 Pt 1):1285–1292. doi: 10.1002/lary.5541011206. [DOI] [PubMed] [Google Scholar]
  9. Blank A. L., Davis G. L., VanDeWater T. R., Ruben R. J. Acute Streptococcus pneumoniae meningogenic labyrinthitis. An experimental guinea pig model and literature review. Arch Otolaryngol Head Neck Surg. 1994 Dec;120(12):1342–1346. doi: 10.1001/archotol.1994.01880360040008. [DOI] [PubMed] [Google Scholar]
  10. Camara M., Mitchell T. J., Andrew P. W., Boulnois G. J. Streptococcus pneumoniae produces at least two distinct enzymes with neuraminidase activity: cloning and expression of a second neuraminidase gene in Escherichia coli. Infect Immun. 1991 Aug;59(8):2856–2858. doi: 10.1128/iai.59.8.2856-2858.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Canvin J. R., Marvin A. P., Sivakumaran M., Paton J. C., Boulnois G. J., Andrew P. W., Mitchell T. J. The role of pneumolysin and autolysin in the pathology of pneumonia and septicemia in mice infected with a type 2 pneumococcus. J Infect Dis. 1995 Jul;172(1):119–123. doi: 10.1093/infdis/172.1.119. [DOI] [PubMed] [Google Scholar]
  12. Cody A. R., Robertson D., Bredberg G., Johnston B. M. Electrophysiological and morphological changes in the guinea pig cochlea following mechanical trauma to the organ of Corti. Acta Otolaryngol. 1980 May-Jun;89(5-6):440–452. doi: 10.3109/00016488009127160. [DOI] [PubMed] [Google Scholar]
  13. Comis S. D., Osborne M. P., Stephen J., Tarlow M. J., Hayward T. L., Mitchell T. J., Andrew P. W., Boulnois G. J. Cytotoxic effects on hair cells of guinea pig cochlea produced by pneumolysin, the thiol activated toxin of Streptococcus pneumoniae. Acta Otolaryngol. 1993 Mar;113(2):152–159. doi: 10.3109/00016489309135784. [DOI] [PubMed] [Google Scholar]
  14. Dodge P. R., Davis H., Feigin R. D., Holmes S. J., Kaplan S. L., Jubelirer D. P., Stechenberg B. W., Hirsh S. K. Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis. N Engl J Med. 1984 Oct 4;311(14):869–874. doi: 10.1056/NEJM198410043111401. [DOI] [PubMed] [Google Scholar]
  15. Eavey R. D., Gao Y. Z., Schuknecht H. F., Gonzalez-Pineda M. Otologic features of bacterial meningitis of childhood. J Pediatr. 1985 Mar;106(3):402–407. doi: 10.1016/s0022-3476(85)80664-8. [DOI] [PubMed] [Google Scholar]
  16. Eybalin M. Neurotransmitters and neuromodulators of the mammalian cochlea. Physiol Rev. 1993 Apr;73(2):309–373. doi: 10.1152/physrev.1993.73.2.309. [DOI] [PubMed] [Google Scholar]
  17. Fortnum H. M. Hearing impairment after bacterial meningitis: a review. Arch Dis Child. 1992 Sep;67(9):1128–1133. doi: 10.1136/adc.67.9.1128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Friedland I. R., Paris M. M., Hickey S., Shelton S., Olsen K., Paton J. C., McCracken G. H. The limited role of pneumolysin in the pathogenesis of pneumococcal meningitis. J Infect Dis. 1995 Sep;172(3):805–809. doi: 10.1093/infdis/172.3.805. [DOI] [PubMed] [Google Scholar]
  19. Igarashi M., Saito R., Alford B. R., Filippone M. V., Smith J. A. Temporal bone findings in pneumococcal meningitis. Arch Otolaryngol. 1974 Feb;99(2):79–83. doi: 10.1001/archotol.1974.00780030085001. [DOI] [PubMed] [Google Scholar]
  20. Kay R., Palmer A. C., Taylor P. M. Hearing in the dog as assessed by auditory brainstem evoked potentials. Vet Rec. 1984 Jan 28;114(4):81–84. doi: 10.1136/vr.114.4.81. [DOI] [PubMed] [Google Scholar]
  21. Kay R. The site of the lesion causing hearing loss in bacterial meningitis: a study of experimental streptococcal meningitis in guinea-pigs. Neuropathol Appl Neurobiol. 1991 Dec;17(6):485–493. doi: 10.1111/j.1365-2990.1991.tb00751.x. [DOI] [PubMed] [Google Scholar]
  22. Kelly R. T., Farmer S., Greiff D. Neuraminidase activities of clinical isolates of Diplococcus pneumoniae. J Bacteriol. 1967 Jul;94(1):272–273. doi: 10.1128/jb.94.1.272-273.1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kelly R., Greiff D. Toxicity of pneumococcal neuraminidase. Infect Immun. 1970 Jul;2(1):115–117. doi: 10.1128/iai.2.1.115-117.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Leng G., Comis S. D. The effect of potassium on the activity of auditory nerve fibres of the guinea pig cochlea. Acta Otolaryngol. 1979 Jan-Feb;87(1-2):39–46. doi: 10.3109/00016487909126385. [DOI] [PubMed] [Google Scholar]
  25. Maguin E., Duwat P., Hege T., Ehrlich D., Gruss A. New thermosensitive plasmid for gram-positive bacteria. J Bacteriol. 1992 Sep;174(17):5633–5638. doi: 10.1128/jb.174.17.5633-5638.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. O'Toole R. D., Goode L., Howe C. Neuraminidase activity in bacterial meningitis. J Clin Invest. 1971 May;50(5):979–985. doi: 10.1172/JCI106591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. O'Toole R. D., Stahl W. L. Experimental pneumococcal meningitis. Effects of neuraminidase and other pneumococcal constituents on cerebrospinal fluid in the intact dog. J Neurol Sci. 1975 Oct;26(2):167–178. doi: 10.1016/0022-510x(75)90029-5. [DOI] [PubMed] [Google Scholar]
  28. Osborne M. P., Comis S. D. High resolution scanning electron microscopy of stereocilia in the cochlea of normal, postmortem, and drug-treated guinea pigs. J Electron Microsc Tech. 1990 Jul;15(3):245–260. doi: 10.1002/jemt.1060150305. [DOI] [PubMed] [Google Scholar]
  29. Osborne M. P., Comis S. D., Tarlow M. J., Stephen J. The cochlear lesion in experimental bacterial meningitis of the rabbit. Int J Exp Pathol. 1995 Oct;76(5):317–330. [PMC free article] [PubMed] [Google Scholar]
  30. Paton J. C. The contribution of pneumolysin to the pathogenicity of Streptococcus pneumoniae. Trends Microbiol. 1996 Mar;4(3):103–106. doi: 10.1016/0966-842X(96)81526-5. [DOI] [PubMed] [Google Scholar]
  31. Quagliarello V., Scheld W. M. Bacterial meningitis: pathogenesis, pathophysiology, and progress. N Engl J Med. 1992 Sep 17;327(12):864–872. doi: 10.1056/NEJM199209173271208. [DOI] [PubMed] [Google Scholar]
  32. Rask-Andersen H., Stahle J., Wilbrand H. Human cochlear aqueduct and its accessory canals. Ann Otol Rhinol Laryngol Suppl. 1977 Sep-Oct;86(5 Pt 2 Suppl 42):1–16. doi: 10.1177/00034894770860s501. [DOI] [PubMed] [Google Scholar]
  33. Rayner C. F., Jackson A. D., Rutman A., Dewar A., Mitchell T. J., Andrew P. W., Cole P. J., Wilson R. Interaction of pneumolysin-sufficient and -deficient isogenic variants of Streptococcus pneumoniae with human respiratory mucosa. Infect Immun. 1995 Feb;63(2):442–447. doi: 10.1128/iai.63.2.442-447.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Richardson M. P., Reid A., Tarlow M. J., Rudd P. T. Hearing loss during bacterial meningitis. Arch Dis Child. 1997 Feb;76(2):134–138. doi: 10.1136/adc.76.2.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rubins J. B., Charboneau D., Fasching C., Berry A. M., Paton J. C., Alexander J. E., Andrew P. W., Mitchell T. J., Janoff E. N. Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia. Am J Respir Crit Care Med. 1996 Apr;153(4 Pt 1):1339–1346. doi: 10.1164/ajrccm.153.4.8616564. [DOI] [PubMed] [Google Scholar]
  36. Slepecky N. Overview of mechanical damage to the inner ear: noise as a tool to probe cochlear function. Hear Res. 1986;22:307–321. doi: 10.1016/0378-5955(86)90107-3. [DOI] [PubMed] [Google Scholar]
  37. Wald E. R., Kaplan S. L., Mason E. O., Jr, Sabo D., Ross L., Arditi M., Wiedermann B. L., Barson W., Kim K. S., Yogov R. Dexamethasone therapy for children with bacterial meningitis. Meningitis Study Group. Pediatrics. 1995 Jan;95(1):21–28. [PubMed] [Google Scholar]
  38. Wiedermann B. L., Hawkins E. P., Johnson G. S., Lamberth L. B., Mason E. O., Kaplan S. L. Pathogenesis of labyrinthitis associated with Haemophilus influenzae type b meningitis in infant rats. J Infect Dis. 1986 Jan;153(1):27–32. doi: 10.1093/infdis/153.1.27. [DOI] [PubMed] [Google Scholar]
  39. Winter A. J., Marwick S., Osborne M., Comis S., Stephen J., Tarlow M. Ultrastructural damage to the organ of corti during acute experimental Escherichia coli and pneumococcal meningitis in guinea pigs. Acta Otolaryngol. 1996 May;116(3):401–407. doi: 10.3109/00016489609137864. [DOI] [PubMed] [Google Scholar]
  40. Yother J., McDaniel L. S., Briles D. E. Transformation of encapsulated Streptococcus pneumoniae. J Bacteriol. 1986 Dec;168(3):1463–1465. doi: 10.1128/jb.168.3.1463-1465.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]

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