Innate Immunity Evasion Through D-Amino Acid Sequestration

Abstract

The innate immune system functions to limit the spread of bacteria during an infection. This is achieved through a highly complex assault on infiltrating pathogens. One such mechanism is the production of reactive oxygen species. D-amino acid oxidase is an emerging player in the innate immunity as it is capable of producing bactericidal concentrations of reactive oxygen species. Pathogens have evolved an array of strategies to protect themselves against the innate immune system. This work focusses on two bacteria relevant to human health that have evolved two distinct D-amino acid transporters to evade reactive oxygen species produced by D-amino acid oxidase. The Salmonella specific gene, DalS, was found to be co-regulated with the Salmonella Pathogenicity Island-2, a known virulence determinant. DalS is the periplasmic binding domain of a D-alanine ATP Binding Cassette transporter capable of sequestering substrate away from D-amino acid oxidase during Salmonella-neutrophil infections. This work demonstrates a novel host-pathogen interaction that enhances Salmonella survival during an infection. The second transporter, cycA, is conserved across diverse taxa and transports D-alanine and D-serine. This work determined that uropathogenic E. coli uses CycA to sequester D-serine away from DAO during ascending urinary tract infections, and moreover provides another example of how pathogens protect themselves against DAO. Together, these findings contribute to the understanding of the intricate set of virulence strategies of two pathogens that have a significant impact on human health worldwide.