Virulent gamma-glutamyltranspeptidase expression by helicobacter saguini, an enterohepatic helicobacter species isolated from cotton top tamarins with chronic colitis and colon cancer

Abstract

Helicobacter saguini is a novel enterohepatic Helicobacter species isolated from the colon and feces of captive cotton top tamarins with chronic colitis and colon cancer. Mono-associated H. saguini infection in gnotobiotic IL-10 knockout mice causes inflammatory bowel disease and pro-carcinogenic changes to the large intestine. Genomic and biochemical characterization suggest H. saguini may express gamma-glutamyltranspeptidase (GGT), a constitutively expressed periplasmic enzyme that metabolizes extracellular glutamine and glutathione for import as nutrients. GGT activity by other pathogenic Helicobacter spp. and Campylobacter spp., including H. pylori, exhibits virulent effects including inhibition of cellular proliferation, immunomodulation, host colonization persistence, and promotion of inflammatory-mediated pathologies including cancer. In this paper, we use molecular biology, biochemical, and cell culture methods to demonstrate that H. saguini expresses an enzymatically active and virulent functional ggt gene. Multi-sequence alignments indicate that GGT from H. saguini is most homologous to the GGT expressed by H. bilis. GGT from H. saguini inhibited gastrointestinal epithelial and lymphocytes proliferation without evidence of cell death. Additionally, GGT from H. saguini induced pro-inflammatory gene expression in colon epithelial cells. This data indicates H. saguini may utilize GGT expression as an important virulence factor to enable infection and elicit chronic gastrointestinal inflammation.