Perny Michael, Roccio Marta, Grandgirard Denis, Solyga Magdalena, Senn Pascal, Leib Stephen L
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.
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.
J Neurosci. 2016 Jul 20;36(29):7740-9. doi: 10.1523/JNEUROSCI.0554-16.2016.
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.
听力损失是肺炎球菌性脑膜炎（PM）的重要后遗症，在高达30%的幸存者中出现。迄今为止，感染严重程度对PM继发的耳蜗听力功能和病理形态学后果的作用尚未得到研究。我们使用一个成熟的PM模型，系统地研究了耳蜗中神经感觉细胞（即毛细胞和螺旋神经节神经元（SGN））的功能性听力结果和长期命运，重点关注它们的音频定位分布。用递增接种量的肺炎链球菌对幼鼠进行脑池内感染，导致急性疾病时脑脊液中白细胞介素-1β、白细胞介素-6、肿瘤坏死因子α、白细胞介素-10和干扰素-γ水平呈剂量依赖性增加。通过听觉脑干反应记录测量，感染后3周的长期听力损失严重程度与初始接种剂量以及PM急性期测定的促炎细胞因子水平相关。定量耳蜗组织形态学显示，SGN和外毛细胞显著丢失，这与感染程度密切相关，耳蜗底部受损最严重。整个耳蜗内的内毛细胞（IHC）未受到显著影响。然而，存活的IHC在所有耳蜗区域与剩余的SGN失去了突触连接。这些发现证明接种物浓度，即感染严重程度，是耳蜗中长期形态学细胞病变和功能性听力损失的主要决定因素。
听力损失是肺炎球菌性脑膜炎（PM）幸存者中高达30%的患者出现的一种神经功能缺陷。在此，我们分析了肺炎球菌性脑膜炎大鼠模型中感染严重程度与脑脊液中炎症反应、耳蜗中神经感觉病变的音频定位分布以及长期听力功能之间的相关性。我们的研究确定感染严重程度是长期听力损失的关键决定因素，强调了对PM患者及时进行抗生素治疗的重要性。此外，我们的发现详细揭示了耳蜗神经感觉细胞的空间丢失，为脑膜炎相关听力损失的发病机制提供了新见解，揭示了耳保护疗法开发的新起点。
