Regulation of vacuolar pH and its modulation by some microbial species

Abstract

To survive within the host, pathogens such as Mycobacterium tuberculosis and Helicobacter pylori need to evade the immune response and find a protected niche where they are not exposed to microbicidal effectors. The pH of the microenvironment surrounding the pathogen plays a critical role in dictating the organism's fate. Specifically, the acidic pH of the endocytic organelles and phagosomes not only can affect bacterial growth directly but also promotes a variety of host microbicidal responses. The development of mechanisms to avoid or resist the acidic environment generated by host cells is therefore crucial to the survival of many pathogens. Here we review the processes that underlie the generation of organellar acidification and discuss strategies employed by pathogens to circumvent it, using M. tuberculosis and H. pylori as examples.

FIG. 1.

Regulation of organellar acidification. (A) Endocytic vesicles quickly acquire V-ATPases through fusion with early endosomes. V-ATPases use the energy of ATP hydrolysis to accumulate protons in the lumen. The concomitant translocation of counterions, e.g., Cl⁻, via conductive pathways curtails the buildup of a transmembrane electrical potential and allows the luminal accumulation of protons. Proton (equivalent) leakage pathways limit the extent of acidification, while intracellular buffers (B) dictate the rate of acidification. When present, Na⁺/K⁺-ATPases can contribute to the electrical potential across the endosomal membrane, tending to reduce the rate of proton pumping. Na⁺ accumulated in the lumen by the Na⁺/K⁺-ATPases could in turn drive Na⁺/H⁺ exchange, promoting acidification. (B) Schematic representation of the pHs of the main compartments of the secretory (left) and endocytic (right) pathways. The cytosolic pH is also shown, for comparison.

FIG. 2.

Phagosome maturation and mechanisms of evasion. (A) Phagocytosis of nonpathogenic particles follows a pathway that resembles endosomal progression, characterized by progressive acidification of the lumen to a pH of >5 and delivery of lytic enzymes and other microbicidal factors that kill and degrade the contents. (B to E) Some pathogenic bacteria have evolved mechanisms to evade killing. These strategies include inhibition of phagosome maturation and acidification (B); development of resistance to the acidic and lytic environment of phagolysosomes (C); rupture of the phagosome, enabling the pathogens to gain access to the cytoplasm (D); and redirection of phagosomal maturation, with fusion to other, nonmicrobicidal compartments, such as the endoplasmic reticulum or Golgi complex (E).

FIG. 3.

Mechanisms of survival and evasion in Helicobacter pylori. (A) Urea, which is present in the stomach, is transported through UreI into the bacterial cytoplasm, where urease converts it into NH₃ and CO₂. NH₃ quickly diffuses into the periplasm, where it prevents the accumulation of protons by generating NH₄⁺, thereby regulating the periplasmic pH. (B) H. pylori also secretes a cytotoxin called VacA that oligomerizes to form a Cl⁻ channel. When inserted into the phagosomal membrane, VacA contributes to the permeation of counterions that serve to collapse the electrical potential generated by the V-ATPase. Dissipation of the electrical potential promotes proton accumulation. Formation of NH₃ by the bacterial urease serves to sequester incoming protons by forming NH₄⁺. Together with Cl⁻, the accumulated NH₄⁺ acts to increase the osmotic content of the phagosomal lumen. This, in turn, drives the influx of osmotically obliged water, causing swelling of phagosomes into megasomes.