Rational identification of Corynebacterium strains for use as probiotics

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Project Summary Pneumonia is the leading infectious killer of children. Bacterial pathogens, particularly Streptococcus pneumoniae, cause the most serious disease and mortality. Vaccination reduces invasive diseases such as bacteremia and meningitis caused by vaccine serotypes. However, vaccination does not equally lower the burden of pneumonia, and non-vaccine S. pneumoniae serotypes continue to emerge to cause respiratory and invasive infections. Thus, an opportunity exists for new ways to prevent these infections. Nasopharyngeal colonization precedes bacterial pneumonia and other respiratory infections, and the microbiota serves as a barrier to pathogen colonization and subsequent invasion of the lower respiratory tract. Our studies and others demonstrate that commensal, non-pathogenic Corynebacterium species are associated with a lower prevalence of colonization by bacterial respiratory pathogens, including S. pneumoniae. The data show an inverse correlation between the relative abundance of Corynebacterium in the nasopharyngeal microbiota and the risk of colonization by S. pneumoniae. These Corynebacterium species may be promising biotherapeutic candidates for development if they exert specific mechanistic control of bacterial respiratory pathogens. The overall objective herein is to identify the mechanisms by which Corynebacterium spp. colonize the human nasopharynx and exclude S. pneumoniae colonization. The rationale is that defining the mechanisms of these interspecies interactions will lead to identifying Corynebacterium spp. that exert multiple mechanisms of pathogen exclusion and are candidates for future biotherapeutics to prevent respiratory infections. The Specific Aims are: 1) Identify mechanisms by which Corynebacterium spp. adhere to the respiratory epithelium and inhibit Sp colonization through competitive adherence, and 2) Elucidate non-adherence mechanisms by which Corynebacterium spp. inhibit Sp colonization. This proposal will combine models of bacteria-host and bacteria-bacteria interactions to define mechanisms through which Corynebacterium inhibit S. pneumoniae colonization. We will leverage comparative genomics of a large Corynebacterium strain repository to identify accessory gene candidates that mediate respiratory epithelium attachment, competitive adherence with S. pneumoniae, and pneumococcal growth inhibition through secreted factors. The impact of this work is expected from the mechanistic insights and Corynebacterium strain identification that may lead to the first rationally-designed biotherapeutics to prevent pneumonia and other respiratory infections.