title: The Severity of Infection Determines the Localization of Damage and Extent of Sensorineural Hearing Loss in Experimental Pneumococcal Meningitis.
abstract: Hearing loss is an important sequela of pneumococcal meningitis (PM), occurring in up to 30% of survivors. The role of the severity of infection on hearing function and pathomorphological consequences in the cochlea secondary to PM have not been investigated to date. Using a well-established model of PM, we systematically investigated the functional hearing outcome and the long-term fate of neurosensory cells in the cochlea, i.e., hair cells and spiral ganglion neurons (SGNs), with a focus on their tonotopic distribution. Intracisternal infection of infant rats with increasing inocula of Streptococcus pneumoniae resulted in a dose-dependent increase in CSF levels of interleukin-1β, interleukin-6, tumor necrosis factor α, interleukin-10, and interferon-γ in acute disease. The severity of long-term hearing loss at 3 weeks after infection, measured by auditory brainstem response recordings, correlated to the initial inoculum dose and to the levels of proinflammatory cytokines determined in the acute phase of PM. Quantitative cochlear histomorphology revealed a significant loss of SGNs and outer hair cells that strongly correlated to the level of infection, with the most severe damage occurring in the basal part of the cochlea. Inner hair cells (IHCs) were not significantly affected throughout the entire cochlea. However, surviving IHCs lost synaptic connectivity to remaining SGNs in all cochlear regions. These findings provide evidence that the inoculum concentration, i.e., severity of infection, is the major determinant of long-term morphological cell pathologies in the cochlea and functional hearing loss.
  
  
  
  Hearing loss is a neurofunctional deficit occurring in up to 30% of patients surviving pneumococcal meningitis (PM). Here, we analyze the correlation between the severity of infection and the inflammatory response in the CSF, the tonotopic distribution of neurosensory pathologies in the cochlea, and the long-term hearing function in a rat model of pneumococcal meningitis. Our study identifies the severity of infection as the key determinant of long-term hearing loss, underlining the importance of the prompt institution of antibiotic therapy in patients suffering from PM. Furthermore, our findings reveal in detail the spatial loss of cochlear neurosensory cells, providing new insights into the pathogenesis of meningitis-associated hearing loss that reveal new starting points for the development of otoprotective therapies.
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland, Laboratory of Inner Ear Research, Department of Clinical Research, University of Bern and University Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, 3008 Bern, Switzerland, Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Michael
authors.identifier: 0000-0001-5467-6522
authors.initials: M
authors.lastname: Perny
authors.affiliation: Laboratory of Inner Ear Research, Department of Clinical Research, University of Bern and University Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, 3008 Bern, Switzerland, Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Roccio
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland, Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Denis
authors.identifier: 0000-0002-4151-5196
authors.initials: D
authors.lastname: Grandgirard
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland, Laboratory of Inner Ear Research, Department of Clinical Research, University of Bern and University Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, 3008 Bern, Switzerland, Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Magdalena
authors.identifier: 0000-0003-2969-2963
authors.initials: M
authors.lastname: Solyga
authors.affiliation: Laboratory of Inner Ear Research, Department of Clinical Research, University of Bern and University Department of Otorhinolaryngology, Head & Neck Surgery, Inselspital, 3008 Bern, Switzerland, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Geneva, 1205 Geneva, Switzerland, and Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland.
authors.forename: Pascal
authors.identifier: 0000-0002-4619-3341
authors.initials: P
authors.lastname: Senn
authors.affiliation: Neuroinfection Laboratory, Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland, Cluster for Regenerative Neuroscience, Department of Clinical Research, University of Bern, 3008 Bern, Switzerland stephen.leib@ifik.unibe.ch.
authors.forename: Stephen L
authors.identifier: 0000-0002-1106-6123
authors.initials: SL
authors.lastname: Leib
mesh_terms: D000161:Acoustic Stimulation; D000429:Alcohol Oxidoreductases; D000818:Animals; D000831:Animals, Newborn; D056970:Co-Repressor Proteins; D003051:Cochlea / Q000473:pathology; D016207:Cytokines / Q000134:cerebrospinal fluid* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005260:Female; D006198:Hair Cells, Auditory / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008586:Meningitis, Pneumococcal / Q000150:complications*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013136:Spiral Ganglion / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000502:physiology
chemical_list: D056970:Co-Repressor Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse
keywords: animal model; hair cells; pneumococcal meningitis; sensorineural hearing loss; spiral ganglion neurons; streptococcus pneumonia