The Role of Toll-Like Receptor 9 in Helicobacter pylori-Mediated Inflammation and Carcinogenesis

Abstract

CANCER BIOLOGY

The Role of Toll-Like Receptor 9 in Helicobacter pylori-Mediated Inflammation and Carcinogenesis

Matthew Gordon Varga

Dissertation under the direction of Dr. Richard M. Peek Jr., MD

Helicobacter pylori is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. The H. pylori cag pathogenicity island encodes a type IV secretion system (T4SS), which translocates the pro-inflammatory protein CagA into host cells. Although T4SSs are ubiquitous and facilitate transport of diverse effectors from bacterial cells to the eukaryotic host, only two bacterial species have been shown to translocate DNA into eukaryotic host cells. Furthermore, in DNA-translocating T4SSs, the only proteins transported via the T4SS are proteins associated with the process of DNA transfer. Toll-like receptor 9 is an endosome bound, innate immune receptor that detects hypomethylated CpG DNA motifs. We now demonstrate that the H. pylori cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Genetic deficiency of Tlr9 augments the intensity of IL-17-driven immune responses to H. pylori in vivo, suggesting that engagement of TLR9 by bacterial DNA leads to suppression of inflammation, which may accommodate long-term interactions between pathogenic H. pylori and the gastric epithelium. In support of this hypothesis, analysis of a human population at increased risk for gastric cancer revealed that levels of H. pylori-mediated TLR9 activation were directly related to the severity of cancer risk. These results demonstrate the ever-increasing versatility of T4SS machineries and their involvement in promoting pathogen persistence and modulating disease outcomes.