Molecular Mechanisms of Helicobacter Pylori Trans-kingdom DNA Conjugation

Of the recognized infection-associated malignancies, the most significant carcinogenic microbe is the gastric bacterium Helicobacter pylori, which chronically colonizes the stomach of over half of the global population and contributes to the development of more than one million new cases of cancer per year. Despite many decades of research, we do not fully understand how H. pylori balances interactions with the human host to stimulate the development of gastric disease. The cancer-associated H. pylori cag type IV secretion system (cag T4SS) has emerged as a paradigm for understanding how a single molecular device transports diverse immunostimulatory cargo into target eukaryotic cells. Whereas some T4SSs have the capacity to secrete multiple protein effectors, the ability to translocate a pro-inflammatory bacterial oncoprotein and a repertoire of DNA and polysaccharide substrates distinguishes the cag T4SS from other nanomachines. In exciting new studies, we discovered that cag T4SS-dependent trans-kingdom DNA conjugation stimulates cytosolic nucleic acid reconnaissance systems to provoke the production of multifarious interferons and inflammatory cytokines that orchestrate diverse immune responses. Our long-term objective is to mechanistically characterize how the dynamic cag T4SS transports carcinogenic molecular cargo into gastric cells. Towards our objective, we aim to define the kinetics and biogeography of cag T4SS-dependent DNA translocation in vivo and delineate the mechanism by which chromosomal DNA cargo is excised and coupled to the cag T4SS apparatus. Our studies will employ rodent infection models, high-resolution microscopy, biochemical approaches, and immunological assays to address longstanding knowledge gaps in gastric cancer biology and uncover microbial mechanisms that are involved in the development of pre-malignant lesions. Collectively, these investigations will advance our understanding of important host-pathogen conflicts that engage nucleic acid surveillance pathways to regulate host immunity and trigger microbial carcinogenesis. Furthermore, our studies will provide the foundational framework for developing new treatment and intervention strategies to reduce the incidence and severity of malignancies that arise as a consequence of infection-induced chronic inflammation.