Helicobacter pylori actively suppresses innate immune nucleic acid receptors
Samuel D R Dooyema1,2, Jennifer M Noto3, Lydia E Wroblewski3
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Abstract:
Chronic mucosal pathogens have evolved multiple strategies to manipulate the host immune response; consequently, microbes contribute to the development of >2 million cases of cancer/year. Gastric adenocarcinoma is the fourth leading cause of cancer-related death and Helicobacter pylori confers the highest risk for this disease. Gastric innate immune effectors can either eliminate bacteria or mobilize adaptive immune responses including Toll-like receptors (TLRs), and cytosolic DNA sensor/adaptor proteins (e.g., stimulator of interferon genes, STING). The H. pylori strain-specific cag type IV secretion system (T4SS) augments gastric cancer risk and translocates DNA into epithelial cells where it activates the microbial DNA sensor TLR9 and suppresses injury in vivo; however, the ability of H. pylori to suppress additional nucleic acid PRRs within the context of chronic gastric inflammation and injury remains undefined. In this study, in vitro and ex vivo experiments identified a novel mechanism through which H. pylori actively suppresses STING and RIG-I signaling via downregulation of IRF3 activation. In vivo, the use of genetically deficient mice revealed that Th17 inflammatory responses are heightened following H. pylori infection within the context of Sting deficiency in conjunction with increased expression of a known host immune regulator, Trim30a. This novel mechanism of immune suppression by H. pylori is likely a critical component of a finely tuned rheostat that not only regulates the initial innate immune response, but also drives chronic gastric inflammation and injury.
Insights
Helicobacter pylori infection suppresses key immune pathways, including stimulator of interferon genes (STING) signaling, contributing to chronic gastric inflammation and cancer risk. This immune evasion mechanism is crucial for pathogen survival and disease progression.
Area of Science:
- Immunology
- Microbiology
- Gastroenterology
Background:
- Chronic mucosal pathogens manipulate host immunity, contributing to over 2 million cancer cases annually.
- Helicobacter pylori is a major risk factor for gastric adenocarcinoma, the fourth leading cause of cancer death.
- H. pylori utilizes the cag type IV secretion system to translocate bacterial DNA, activating TLR9 and suppressing injury.
Purpose of the Study:
- To investigate the role of H. pylori in suppressing additional nucleic acid pattern recognition receptors (PRRs) during chronic gastric inflammation.
- To elucidate the mechanism by which H. pylori evades host innate immune detection.
- To understand the impact of H. pylori-mediated immune suppression on gastric cancer development.
Main Methods:
- In vitro and ex vivo experiments to assess H. pylori's effect on STING and RIG-I signaling.
- In vivo studies using genetically deficient mice to analyze inflammatory responses.
- Analysis of IRF3 activation and Trim30a expression in response to H. pylori infection.
Main Results:
- H. pylori actively suppresses STING and RIG-I signaling by downregulating IRF3 activation.
- Sting-deficient mice infected with H. pylori exhibit heightened Th17 inflammatory responses.
- Increased expression of the immune regulator Trim30a was observed in Sting-deficient mice.
Conclusions:
- H. pylori employs a novel immune suppression mechanism involving the downregulation of STING and RIG-I signaling.
- This immune evasion contributes to chronic gastric inflammation and injury, increasing cancer risk.
- H. pylori's manipulation of innate immunity is a critical factor in driving gastric pathogenesis.
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