Abstract
Sensorineural hearing loss is the most common long-term deficit after pneumococcal meningitis (PM), occurring in up to 30% of surviving patients. The infection and the following overshooting inflammatory host response damage the vulnerable sensory cells of the inner ear, resulting in loss of hair cells and spiral ganglion neurons, ultimately leading to elevated hearing thresholds. Here, we tested the oto-protective properties of the small heat shock protein alpha B-crystallin (HspB5) with previously reported anti-inflammatory, anti-apoptotic and neuroprotective functions, in an experimental model of PM-induced hearing loss. We analyzed the effect of local and systemic delivery of HspB5 in an infant rat model of PM, as well as ex vivo, using whole mount cultures. Cytokine secretion profile, hearing thresholds and inner ear damage were assessed at predefined stages of the disease up to 1 month after infection. PM was accompanied by elevated pro-inflammatory cytokine concentrations in the cerebrospinal fluid (CSF), leukocyte and neutrophil infiltration in the perilymphatic spaces of the cochlea with neutrophils extracellular trap formation during the acute phase of the disease. Elevated hearing thresholds were measured after recovery from meningitis. Intracisternal but not intraperitoneal administration of HspB5 significantly reduced the levels of TNF-α, IL-6 IFN-γ and IL-10 in the acute phase of the disease. This resulted in a greater outer hair cell survival, as well as improved hearing thresholds at later stages. These results suggest that high local concentrations of HspB5 are needed to prevent inner ear damage in acute PM. HspB5 represents a promising therapeutic option to improve the auditory outcome and counteract hearing loss after PM.
Highlights
Worldwide around 460 million people suffer from disabling hearing loss
The previously reported anti-inflammatory, anti-apoptotic and neuroprotective effect of the small heat shock protein HspB5 [21, 30, 36, 43, 44] prompted us to examine whether HspB5 could be used as a therapeutic agent to counteract bacterial meningitis-induced damage to the inner ear
Our results demonstrate that intracisternal HspB5 therapy results in an increased outer hair cell survival and improved hearing thresholds after pneumococcal infection
Summary
Worldwide around 460 million people suffer from disabling hearing loss (world health organization fact sheet 2019). This is caused by inherited genetic defects or acquired damage by ototoxic drugs, exposure to excessive noise, aging or certain infectious diseases such as meningitis. Streptococcus pneumoniae is the most common and simultaneously the most severe pathogen causing bacterial meningitis. Pneumococcal meningitis (PM) is associated with high mortality and risk for neurological sequelae, with sensorineural hearing loss representing the most frequent long term deficit [1] occurring in up to 30% of surviving patients [2]. Bacterial meningitis evokes a robust inflammatory response marked by recruitment of leukocytes, mostly polymorphonuclear neutrophils, to the cerebrospinal fluid (CSF) spaces, including the inner ear. For many years the cochlea was thought to be immuneprivileged, but more recent studies have shown that resident macrophages are present in the lateral wall, in the spiral limbus and in the basal side of basilar membrane and are activated after insult [3,4,5,6,7]
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