Biology subjects

Solnick, J. V.

Publications and source records attributed to Solnick, J. V..

3 recordsLinked to original sources

bioRxiv2025

CagY sequence and structural motifs are associated with ancestry and 1 disease in world-wide Helicobacter pylori strains

Helicobacter pylori (Hp) interacts with gastric epithelial cells using a multi-protein type 4 secretion system (T4SS) whose function is regulated by CagY. CagY is the T4SS backbone, connecting the bacterial cytoplasm with the epithelial cytoplasm and interacting with most other T4SS proteins. However, its mechanisms of action are unknown. We aimed to comprehensively analyse cagY in a worldwide collection of strains to unmask any correlation between ancestry and/or disease and sequence diversity, including an analysis of critical domains and associated structural changes. We used 674 cagY sequences derived from1,012 Hp genomes, sequenced with Single Molecule Real-Time from the Hp Genome Project. Phylogenetic and principal component analyses (PCA) revealed a strong population structure among European, Asian, African and American clusters, which interfered with other analyses. To address this heterogeneity, dimensional reduction analysis with PCA and Linear Discriminant Analyses were used to minimize interference before studying possible association of cagY diversity with disease. For this analysis, cagY genes were fragmented using unitig-caller with a designed analytical pipeline that clearly separated the non-atrophic gastritis (NAG), advanced intestinal metaplasia and gastric cancer (GC) groups. Sixty-four unitigs significantly separated GC from NAG based on cagY sequences, and the most GC-associated unitigs were localized in the middle repeat region of the protein (MRR), particularly in the A module, including the cysteine-containing motif YLDCVSQ. Proline was enriched in the MRR and VirB10 regions. The consequences of the diversity on the protein structure were analysed using ChimeraX. The validated and stabilized 14-multimer model showed major structural changes along the multimer-structure, particularly in the cysteine-rich MRR region, that might be one mechanism by which CagY regulates T4SS function.

bioinformatics↗

bioRxiv2023

Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer

Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.

immunology↗

bioRxiv2018

CagY-dependent regulation of type IV secretion in Helicobacter pylori is associated with alterations in integrin binding

Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4+ T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human 5{beta}1 integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to 5{beta}1 integrin. Using a cell-free microfluidic assay, we found that H. pylori binding to 5{beta}1 integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed when H. pylori is in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to 5{beta}1 integrin. Bacteria with variant cagY alleles that reduced T4SS function showed comparable reduction in binding to 5{beta}1 integrin, though CagY was still expressed on the bacterial surface. We speculate that cagY-dependent modulation of H. pylori T4SS function is mediated by alterations in binding to 5{beta}1 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection.\n\nIMPORTANCEInfection with H. pylori can cause peptic ulcers, and is the most important risk factor for gastric cancer, the third most common cause of cancer death worldwide. The major H. pylori virulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We previously showed that recombination in CagY, an essential T4SS component, modulates the function of the T4SS. Here we found that these recombination events produce parallel changes in specific binding to 5{beta}1 integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. We propose that CagY-dependent binding to 5{beta}1 integrin acts like a molecular rheostat that alters T4SS function and modulates the host immune response to promote persistent infection.

microbiology↗