Research Focus

Thesis Project Title: Commensal E. Coli Induced Colonization Resistance Against Mucosal Salmonella Infection

Salmonella enterica serovar Typhimurium is a leading cause of gastroenteritis worldwide. Salmonella’s flagellin induces an innate immune response that is dependent on an Naip5/Nlrc4/Casp1inflammasome. We hypothesized that the Naip5 inflammasome was critical for detection of flagellin and protection against mucosal Salmonella infection. We demonstrate that during systemic infection, Salmonella efficiently evades flagellin detection by Naip5. Paradoxically during mucosal infections, Naip5-/- mice were protected from Salmonella infection, which was independent of flagellin expression by Salmonella. This protection against Salmonella infection was not inherited as a simple Mendelian trait, but transmitted to all progeny regardless of the Naip5 genotype. Transmission of microbiota from Naip5-/- to WT C57BL/6 mice was sufficient to transfer protection. The Naip5-/- colony was noted to harbor Trichomonas, a possible mediator of this phenotype. Treatment of Naip5-/- mice with metronidazole eliminated Trichomonas, but paradoxically augmented protection. The enhanced protection was associated with outgrowth of a commensal Escherichia coli strain. Further studies demonstrate this commensal E. coli strain (E. coli XZ) is capable of transmitting colonization resistance), and that this protection is independent TLR5/inflammasome, MyD88, adaptive immunity, and a complex microbiome. Our studies illuminate the complexity of mucosal infections, where the multitude of interactions between microbiota, pathogens and the innate immune system shape host defenses.