- Helicobacter pylori strain HPAG1 is a well-characterized clinical isolate obtained from a patient with gastric adenocarcinoma in the United States. It belongs to the hpEurope population and was among the first H. pylori strains to be fully sequenced after the prototypical strains 26695 and J99.
- HPAG1 is of particular interest due to its association with malignancy, and it has contributed significantly to comparative genomic studies seeking to link specific bacterial genotypes with cancer risk. The complete genome of HPAG1 has provided insight into the diversity and plasticity of H. pylori virulence factors, especially in the context of strains isolated from patients with advanced gastric pathology.
- A defining feature of HPAG1 is the presence of an intact and functional cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) responsible for translocating the CagA oncoprotein into host epithelial cells. The CagA protein in HPAG1 is of the Western-type, containing EPIYA-A, -B, and -C motifs, which, when phosphorylated, interfere with host cell signaling by activating phosphatases such as SHP-2. These interactions result in cytoskeletal rearrangements, cell elongation (“hummingbird” phenotype), junctional disruption, and increased secretion of pro-inflammatory cytokines, especially interleukin-8 (IL-8). The ability of HPAG1 to robustly activate these pathways aligns with its origin from a cancer patient and underscores its utility in studying oncogenic transformation.
- HPAG1 also produces a highly active form of the Vacuolating cytotoxin A (VacA), with the s1/m1 genotype, associated with strong vacuolating activity in epithelial cells. VacA contributes to tissue damage, promotes immune evasion by interfering with T-cell activation, and affects mitochondrial function. The combined action of CagA and VacA in HPAG1 leads to synergistic damage to gastric epithelial integrity and promotes a pro-carcinogenic microenvironment. These virulence factors have made HPAG1 a preferred model for dissecting the molecular mechanisms of gastric epithelial injury and carcinogenesis.
- In addition to CagA and VacA, HPAG1 expresses several outer membrane proteins (OMPs), including BabA, which mediates adherence to Lewis b blood group antigens on gastric epithelial cells. Adherence is crucial for efficient delivery of CagA and for bacterial persistence. HPAG1 also contains other adhesins such as HopQ and OipA, although their expression may vary due to phase variation, a common regulatory mechanism in H. pylori. These adhesins contribute to tissue tropism, immune modulation, and chronic colonization, which are all central to the development of long-term infection and, ultimately, disease progression.
- The genome of HPAG1 has also revealed insights into H. pylori’s plasticity zones, regions of high genetic variability that often harbor strain-specific virulence or metabolic genes. Compared to the 26695 and J99 strains, HPAG1 contains unique sequences in its plasticity region, including genes involved in DNA modification and restriction-modification systems, which may influence genome stability and adaptability. These differences have been important in comparative genomics, helping to delineate genotype-phenotype correlations and understand the evolutionary pathways that lead to increased cancer risk.
- In summary, H. pylori strain HPAG1 is a highly virulent, cancer-associated isolate with a functional cagPAI and active VacA, making it an ideal model for studying the mechanisms of gastric inflammation, epithelial transformation, and carcinogenesis. Its genomic features provide valuable information for identifying bacterial determinants linked to disease severity and for exploring how bacterial diversity contributes to clinical outcomes. HPAG1 remains a vital tool in both experimental and comparative studies aimed at unraveling the complex interplay between H. pylori, host factors, and gastric cancer development.
