Isabella Sirit

ADP-heptose-driven NF-kB activation mediates STING suppression by Helicobacter pylori

Helicobacter pylori infection and the ensuing gastric inflammatory response are the strongest known risk factors for gastric cancer, which is the 5th leading cause of cancer-related death in the world. One of the most intensively studied H. pylori strain-specific microbial virulence determinants is the cytotoxin-associated gene (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) that can translocate the oncoprotein CagA, microbial DNA, and LPS precursors, such as ADP-heptose, into host epithelial cells. Microbial DNA classically activates the intracellular DNA sensor stimulator of interferon genes (STING); however, STING deficiency is associated with gastric carcinogenesis and our laboratory has previously demonstrated significant suppression of STING activation following infection with H. pylori in vitro, ex vivo, and in vivo.  RNA-seq data derived from murine gastric tissue further revealed H. pylori-dependent upregulation of a STING inhibitor, TRIM30a. TRIM proteins function as E3 ubiquitin ligases and have the capacity to inhibit STING function. Human validation studies identified additional TRIM proteins that were significantly increased in gastric premalignant lesions. The overarching aim of my project is to define the role that H. pylori ADP-heptose exerts on induction of STING-inhibiting TRIM proteins. 
 

Mentor: Richard M. Peek, Jr., M.D.