The Role of Helicobacter Pylori Adhesin A (HpaA) in Gastrointestinal Diseases

Helicobacter pylori adhesin A (HpaA) is a type of protein known as an adhesin, found in Helicobacter pylori, which helps the bacterium stick to the stomach lining and is associated with various gastrointestinal diseases, including gastritis, peptic ulcers, and gastric cancer. The elucidation of HpaA's crystallographic structure advances our understanding of H pylori pathogenesis but is also a crucial step toward creating new, more effective vaccines and developing targeted derivatives.

Crystallographic analysis revealed that HpaA has a unique, elongated structure, characteristic of the Helicobacteraceae family. It includes the apical domain, which is necessary for the protein to adhere to gastric epithelial cells. Researchers discovered that HpaA triggers macrophages, a type of immune cell, to produce tumor necrosis factor-alpha (TNF-α), a protein that plays a role in inflammation. These findings highlight HpaA's role in H pylori pathogenesis, indicating its involvement in colonization and the immune response.

“To address this ambiguity and gain clarity on the role of HpaA, we capitalized on the purification and labeling of homogeneous HpaA protein samples to conduct direct binding assays between HpaA and AGS cells,” according to investigators. “Our data illustrate the remarkable binding capacity of HpaA to AGS cells, surpassing even the cell association levels of Tipα, a well-known secreted effector of H pylori that interacts with surface nucleolin receptors.”¹

The investigators concentrated on understanding the molecular function and identifying the binding determinants of HpaA, motivated by its role in H pylori's attachment to gastric epithelial cells. The elucidation of HpaA's crystallographic structure at 2.9 Å resolution was achieved, enabling its shape and the specific domains vital to its function in adhesion and modulation of the immune response. This study explored HpaA's role in immunoregulation by evaluating its ability to induce TNF-α expression in macrophages in vitro.

“In relation to the debated neuraminyllactose binding activity, our findings indicate that the association of HpaA with AGS cells (a human gastric adenocarcinoma cell line) is not reliant on neuraminic acid,” according to investigators. “This conclusion is supported by the fact that competition with exogenous sialic acid does not reduce the binding activity, suggesting the involvement of a receptor other than neuraminic acid in mediating host-cell interactions with HpaA adhesins.”¹

Building on the insights gained from studying proteins like HpaA, in 2022, the US Food and Drug Administration (FDA) issued approvals of 2 vonoprazan-based treatments for H pylori infection. Marketed by Phathom Pharmaceuticals under the names Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), the therapies were approved after positive safety and efficacy data from the phase 3 PHALCON-HP trial.

“The approval of VOQUEZNA treatment regimens offers physicians and patients 2 therapeutic options that showed superior eradication rates compared to proton pump inhibitor-based (PPI) lansoprazole triple therapy in the overall patient population in a pivotal trial,” said Terrie Curran, the president and CEO of Phathom. ²

The approval comes on the vonoprazan Prescription Drug User Fee Act date. The FDA previously accepted 2 New Drug Applications for these vonoprazan dual and triple therapy treatments, giving them priority review designation.

This study on HpaA elucidates its structure, function, and impact on immune responses revealing a specific crystal structure for attachment and its role in TNF-α production, advancing understanding of the infection’s pathogenesis. These insights pave the way for treatments like vonoprazan, improving the overall management of H pylori infections.

References

1. Martini C, Araba V, Beniani M, Armoa Ortiz P, Simmons M, et. al. Unraveling the crystal structure of the HpaA adhesin: insights into cell adhesion function and epitope localization of a Helicobacter pylori vaccine candidate. ASM Journals. Published February 20, 2024. Accessed March 26, 2024. doi: https://doi.org/10.1128/mbio.02952-23
2. Cosdon N. FDA Approves 2 Vonoprazan Treatments for Helicobacter Pylori Infection. ContagionLive. Published May 3, 2022. Accessed March 26, 2024. https://www.contagionlive.com/view/fda-approves-2-vonoprazan-treatments-for-helicobacter-pylori-infection