Helicobacter pylori is a spiral-shaped bacterium that has adapted to colonize the human stomach, an environment previously thought to be sterile due to its high acidity. This microorganism causes chronic inflammation of the stomach lining (gastritis) and is a major contributing factor to the development of peptic ulcers globally. Persistent colonization with specific strains is also linked to a higher risk of developing gastric cancer. The bacterium’s success as a long-term colonizer depends on structural adaptations and biochemical mechanisms that allow it to bypass harsh gastric acid and disrupt host cell function.
The Physical Architecture of H. pylori
The bacterium is typically described as an S-shaped or helical rod, measuring approximately 0.5 micrometers wide and up to 5 micrometers long. This distinctive, corkscrew-like morphology is maintained by a specialized cell wall structure that includes peptidoglycan-modifying enzymes. The helical body provides a mechanical advantage that facilitates movement through the highly viscous mucus layer lining the stomach.
Movement is powered by a tuft of sheathed flagella, usually numbering between five and seven, located at one pole of the cell. These multiple, whip-like appendages rotate rapidly, propelling the bacterium forward through the stomach’s viscous environment. The flagella are important for navigating the thick outer layer of gastric mucus to reach the underlying epithelial cells, where the acidity is less intense.
As a Gram-negative bacterium, H. pylori possesses an outer membrane that provides a protective barrier. This outer membrane is composed of phospholipids and lipopolysaccharide, with numerous embedded outer membrane proteins. These proteins serve various functions, including the transport of nutrients and acting as adhesins for initial attachment to the host cells.
Acid Neutralization: The Urease Survival Strategy
Survival in the highly acidic environment of the stomach, which can reach a pH of 1 to 2, is primarily achieved through the action of the urease enzyme. Urease is the most abundant protein produced by the bacterium, accounting for up to 15% of its total protein mass. This nickel-containing enzyme catalyzes the hydrolysis of urea, a compound naturally present in gastric juice, into ammonia and carbonic acid.
The resulting ammonia acts as a strong base, neutralizing the surrounding acid to create a cloud of protection for the bacterium. This localized neutralization raises the pH in the immediate vicinity of the cell, allowing H. pylori to survive and burrow into the protective, near-neutral mucus layer. Without functional urease, the bacterium cannot colonize the stomach effectively.
The enzyme’s activity is precisely regulated by a protein called UreI, an integral membrane protein that functions as a pH-activated urea transporter. When the external environment becomes highly acidic, UreI opens to allow urea to flood into the cell’s cytoplasm, where the main urease pool is located. This mechanism ensures that the ammonia-producing reaction is activated only when needed for acid defense. The UreI-regulated cytoplasmic reaction is the most critical mechanism for initial acid survival.
Virulence Factors and Host Cell Disruption
Once H. pylori has breached the acid barrier and reached the epithelial surface, it employs virulence factors to adhere to and damage the host cells. Adherence is mediated by outer membrane proteins acting as adhesins. Key examples include BabA, which binds to Lewis b blood group antigens on the gastric epithelial cells, and SabA, which targets sialylated glycoproteins. This firm attachment is necessary to withstand the constant flow of gastric contents and to facilitate the delivery of toxins.
A significant pathogenicity mechanism centers on the cag Pathogenicity Island (Cag PAI), which encodes the Type IV Secretion System (T4SS). The T4SS functions like a syringe-like structure, directly injecting the virulence protein CagA into the host cell cytoplasm. Once inside, the CagA protein becomes phosphorylated and hijacks host signaling pathways.
The injected CagA interacts with host cell enzymes, leading to abnormal cell signaling and the disruption of cell-to-cell junctions. This action causes the epithelial cells to scatter, altering the normal tissue architecture and promoting uncontrolled cell proliferation. Another major factor is VacA (Vacuolating Cytotoxin A), a protein that is secreted by the bacterium and then internalized by the host cell. Once internalized, VacA targets the mitochondria and endosomal compartments, causing the formation of large vacuoles within the cell. This vacuolization leads to cell death and the widespread disruption of the epithelial barrier, contributing directly to the inflammation and tissue damage characteristic of chronic H. pylori infection.