This CDA-2 application proposes a 5-year training program to develop the career of Dr. Nicholas Maurice as he investigates mechanisms of Streptococcus pneumoniae pathogenicity with a focus on how the interaction between bacterial virulence factors and host mitochondrial oxidative DNA damage and repair modulates the innate immune response to pneumococcal infection. His primary mentor, Dr. Ruxana Sadikot, is an internationally-recognized expert in the field of host defense against bacterial pathogens. His mentorship team includes other senior investigators at the Atlanta VA and Emory University with complementary areas of expertise that will contribute to Dr. Maurice’s career development. In addition, Dr. Maurice will benefit from an excellent training environment at the Atlanta VA Medical Center and Emory University with a proven track record of success developing the careers of young investigators. Previous published research by Dr. Maurice identified key virulence factors of the bacterial pathogen, Pseudomonas aeruginosa, that impair innate immunity through attenuation of host epithelial cell mitochondrial bioenergetic function and mitochondrial biogenesis. He demonstrated that genetic and pharmacologic strategies that enhanced mitochondrial biogenesis could promote epithelial host defense. Based on his work investigating mitochondrial biogenesis, Dr. Maurice began investigating another mitochondrial quality control process namely mitochondrial DNA repair. He also began focusing on the bacteria S. pneumoniae given the significant health threat it poses to the veteran population. Preliminary research has identified the novel finding that S. pneumoniae induces oxidative mitochondrial DNA damage and attenuates expression of the DNA repair enzyme, OGG1, in host epithelial cells. Additional data suggest that this pathway may have significant consequences on the epithelial host response to pneumococcal infection. This work has led to the hypothesis that pneumococcal virulence factors such as pneumolysin, a cholesterol-dependent cytolysin, impair host defense through oxidative mitochondrial DNA damage, but targeted enhancement of mitochondrial DNA repair can ameliorate cellular dysfunction and improve the host response to pneumococcal infection. This proposal encompasses three aims. First, the pneumococcal virulence factors responsible for the induction of oxidative mitochondrial DNA injury and attenuation of OGG1 expression in host epithelial cells will be identified. Second, the role of reactive oxygen species-mediated mitochondrial damage and OGG1-mediated mitochondrial DNA repair in the epithelial host response to S. pneumoniae will be defined. Third, in pre-clinical translational studies, novel therapeutic strategies targeting mitochondrial OGG1 will be tested in an in vivo model of pneumococcal pneumonia to determine if enhancing mitochondrial DNA repair reflects an efficacious treatment strategy for S. pneumoniae infection. These studies will pr...