Identification of novel components of the defense response to intestinal pathogens using transcriptional profiling of infected tissue

The focus of the work contained within this dissertation is to better define the host response occurring in the gastrointestinal lymphoid tissue (GALT) of mice during infection with the immunomodulatory bacterial pathogens Yersinia enterocolitica and Salmonella enterica. An initial characterization of the oral model of Y. enterocolitica was completed to define basic cellular and molecular components of the immune response. This study provided a platform for large-scale transcriptional analysis studies using Affymetrix GeneChip technology. These studies identified histidine decarboxylase (Hdc) as a gene significantly upregulated in GALT tissue in response to Y. enterocolitica infection. HDC produces the biogenic amine histamine which is best known for its roles in allergy and inflammation. However, little is known about the role of histamine during bacterial infection. Using a pharmacological approach it was determined that histamine signaling through the histamine H2 receptor but not the histamine H1 receptor is important for controlling Y. enterocolitica infection in mice.; The GeneChip data acquired for Y. enterocolitica infection was compared with GeneChip data acquired following S. enterica infection. Both pathogens elicited a general inflammatory response indicated by the upregulation of cytokines and chemokines, coupled with the downregulation of monoxygenases and UDP glucuronosyltransferases. However, specific differences were also observed. Most notably in the transcriptional regulation of gamma interferon (IFN-gamma) and IFN-gamma regulated genes in response to S. enterica but not Y. enterocolitica. Of particular note, matrix metalloproteinase 3 (MMP-3) was found to be upregulated in the Peyer's patches following infection with both pathogens. There was little difference in the survival of MMP-3-/- mice infected with Y. enterocolitica when compared to MMP-3+/+ mice. In contrast, MMP-3-/- mice were markedly more resistant to S. enterica infection than to MMP-3+/+ mice. Tissues and whole serum contained lower amounts of inflammatory cytokines in MMP-3 -/- mice in comparison with MMP-3+/+ mice suggesting that MMP-3 is involved in initiating an early and lethal cytokine response to S. enterica colonization. These studies indicate that large-scale transcriptional analysis of infected tissues is useful for identifying novel components of the host response to bacterial pathogens.