Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis

Abstract

More than 50% of the world's population is infected with Helicobacter pylori (H. pylori). Chronic infection with this Gram-negative pathogen is associated with the development of peptic ulcers and is linked to an increased risk of gastric cancer. H. pylori secretes many proteinaceous factors that are important for initial colonization and subsequent persistence in the host stomach. One of the major protein toxins secreted by H. pylori is the Vacuolating cytotoxin A (VacA). After secretion from the bacteria via a type V autotransport secretion system, the 88 kDa VacA toxin (comprised of the p33 and p55 subunits) binds to host cells and is internalized, causing severe "vacuolation" characterized by the accumulation of large vesicles that possess hallmarks of both late endosomes and early lysosomes. The development of "vacuoles" has been attributed to the formation of VacA anion-selective channels in membranes. Apart from its vacuolating effects, it has recently become clear that VacA also directly affects mitochondrial function. Earlier studies suggested that the p33 subunit, but not the p55 subunit of VacA, could enter mitochondria to modulate organelle function. This raised the possibility that a mechanism separate from pore formation may be responsible for the effects of VacA on mitochondria, as crystallography studies and structural modeling predict that both subunits are required for a physiologically stable pore. It has also been suggested that the mitochondrial effects observed are due to indirect effects on pro-apoptotic proteins and direct effects on mitochondrial morphology-related processes. Other studies have shown that both the p55 and p33 subunits can indeed be efficiently imported into mammalian-derived mitochondria raising the possibility that they could re-assemble to form a pore. Our review summarizes and consolidates the recent advances in VacA toxin research, with focus on the outstanding controversies in the field and the key remaining questions that need to be addressed.

Keywords: Helicobacter pylori; VacA.

Figure 1

VacA, a multi-functional toxin—VacA may produce “vacuoles,” which have traits of late endosomes and early lysosomes; be taken up by the cell and localize to the mitochondria, which may result in apoptosis; bind to a protein on the cell membrane and induce inflammation and; obstruct T-cell activation and proliferation.

Figure 2

VacA allelic diversity and structure—(A) significant allelic diversity exists in three regions of the VacA gene: the signal region (s1 and s2), the intermediate region (i1, i2, and i3) and the mid-region (m1 and m2); (B) the Signal Sequence allows for the passage of the pro-toxin across the inner-bacterial membrane. The passenger toxin domain consists of the N-terminal VacA fragment (p33) and the C-terminal VacA fragment (p55). The auto-transporter domain allows the toxin to translocate across the outer-bacterial membrane by forming a β-barrel. The p33 and p55 fragments may be cleaved from the β-barrel domain at some point during transit to, or in, the extracellular milieu to form the mature virulent subunits. Arrows indicate cleavage sites.

Figure 3

VacA delivery to mitochondria—once internalized by the host cell, VacA may then be released from “vacuoles” for targeting to the mitochondria via 1: VacA anionic channels within “vacuole” membranes and/or; 2: Compromised “vacuole” membranes resulting from osmotic swelling and eventual destruction.