Our bodies are replete with bacteria and other microorganisms that coexist without harming us, but we do occasionally suffer from infections that cause harm. Bacterial infection? No problem—just (responsibly) pop some (prescribed) antibiotic pills (until the end of the course as directed by your doctor), and bam! All better.
Except it doesn’t always work that way, and sometimes the bacteria can cause lasting harm. One particular critter, Helicobacter pylori, infects the stomach and can live there for decades, undetected, but it can cause all manner of problems—and even cancer.
Although H. pylori infects about half of all adults worldwide, infections can go undetected for decades and are the primary risk factor for gastric cancer. Gastric cancer is the fifth most common cause of cancer deaths worldwide. Of the two main types of H. pylori strains that exist, one type is associated with a higher cancer risk than the other.
A chunk of DNA called the cag pathogenicity island is responsible for this difference. The cag PAI imparts H. pylori with components of a structure called the Cag type IV secretion system—referred to as the T4SS—and with a bacterial oncoprotein called CagA. The Cag T4SS transports CagA from the bacteria into host cells. Somehow, the actions of the Cag T4SS and CagA can lead to gastric cancer.
Researchers from the Vanderbilt University Medical Center and Vanderbilt University have figured out how these two elements lead to molecular changes in host tissues that favor the development of gastric cancer. Their results were published in Infection and Immunity last month.
“Our laboratory and others have done extensive studies on proteins encoded by the cag pathogenicity island, including CagA and components of the T4SS,” Tim Cover said. Cover is a professor of medicine and the senior author of the paper. “In this study, which was led by a former graduate student and postdoc in my lab, Jennifer Shuman, we evaluated the contributions of the Cag T4SS and CagA to gastric molecular alterations relevant for carcinogenesis.” Using an animal model, the researchers tested the differences between infections with wild-type H. pylori or H. pylori mutants that had a defective Cag T4SS or that lacked CagA.
Aided by highly specialized tools, and with the help of the Proteomics Core Laboratory and the Imaging Mass Spectrometry Core, the paper’s authors analyzed alterations in proteins and RNA transcripts in the gastric tissues of animals infected with the different strains of H. pylori.
In all, Cover and coauthors detected more than a thousand molecular alterations, plus signs of inflammation, in the gastric tissues of animals infected with a wild-type H. pylori strain—one that contained the intact Cag T4SS and CagA—but not in tissues infected with bacteria without a functional Cag T4SS or CagA. But despite these differences, the mutant H. pylori strains successfully colonized the animals’ stomachs, albeit without detectable pathologic host responses.
“These results provide insight into mechanisms by which H. pylori infection can lead to gastric cancer,” Cover said. “We hope that they can also help us, down the road, identify individuals who have a high likelihood of developing gastric cancer so we can target them for medical intervention.”
Other authors on this paper include researchers from the labs of Tim Cover, Holly Algood, and Kevin Schey, and staff members from the Mass Spectrometry Research Center.
Go deeper
The paper “Helicobacter pylori CagA and Cag type IV secretion system activity have key roles in triggering gastric transcriptional and proteomic alterations” was published in Infection and Immunity in March 2025.
Funding
This research used funds from the National Institutes of Health and the Department of Veterans Affairs. Additional scholarship funds from the Vanderbilt-Ingram Cancer Center and the Vanderbilt Digestive Diseases Research Center helped pay for experiments conducted through the Mass Spectrometry Research Center.
School of Medicine Basic Sciences shared resources
This research made use of the Proteomics Core Laboratory and the Imaging Mass Spectrometry Core, both part of the Mass Spectrometry Research Center.