Host factors influencing early clearance of Streptococcus pneumoniae from the middle ear following invasion from the nasopharynx

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Project Summary This proposal addresses the clinically significant issue of bacterial otitis media (OM), a major source of hospital visits and preventable hearing loss in young children and the most common diagnosis for antibiotic prescriptions in this age group. Streptococcus pneumoniae is one of the two most common causes of bacterial OM, which results from bacterial invasion from the nasopharynx to the middle ear. Despite widespread vaccine use, S. pneumoniae remains a significant OM pathogen, indicating the need for new therapeutic approaches. However, large knowledge gaps remain regarding the host factors which contribute to bacterial OM pathogenesis. To address these knowledge gaps, we developed a new mouse model of S. pneumoniae invasion to the middle ear. This model is based on the clinical observation that viral co-infection increases OM risk in children, and in mice promotes S. pneumoniae invasion. We find that serial administration of the viral dsRNA analog poly(I:C) is sufficient to promote S. pneumoniae invasion to the middle ear. Poly(I:C) induces the production of type I interferons (IFNs), which contribute to S. pneumoniae survival in other tissues. In the first Aim, we address the hypothesis that type I IFNs enhance S. pneumoniae survival in the middle ear. Type I IFNs can induce production of the anti-inflammatory cytokine IL-10, which we recently demonstrated suppresses protection against S. pneumoniae infection in the lung. Here, we investigate whether IL-10 signaling in poly(I:C) treated mice enhances S. pneumoniae survival following middle ear invasion, as well as the impact of IL-10 on middle ear inflammation. Together, these experiments will determine whether type I IFNs contribute to S. pneumoniae OM pathogenesis. In the second Aim, we investigate the importance of the host microbiome. Children treated with antibiotics are susceptible to recurrent bacterial OM, and pathogens including S. pneumoniae are more resistant to antibiotics than many commensal (non-pathogenic) species. In preliminary data, we find that antibiotic treated mice have increased S. pneumoniae invasion and reduced neutrophil recruitment to the middle ear. We investigate the importance of microbiome-dependent neutrophil recruitment for early clearance of S. pneumoniae following middle ear invasion. In the upper airway, the prevalent commensal Corynebacterium has been identified by next-generation sequencing as negatively correlated with OM in children, indicating a potentially protective role. Here, we determine whether Corynebacterium improves protection against S. pneumoniae OM in our mouse model as a first step toward developing new probiotic-based approaches for OM in children. The long-term goal of these studies is to develop novel immunotherapy and/or probiotic strategies to improve the burden of OM disease.