Acidification Activates Toxoplasma gondii Motility and Egress by Enhancing Protein Secretion and Cytolytic Activity

Autor: Nadezhda Svezhova, Vern B. Carruthers, M.S. Roiko
Rok vydání: 2014
Předmět:
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 10, Iss 11, p e1004488 (2014)
ISSN: 1553-7374
Popis: Pathogenic microbes rely on environmental cues to initiate key events during infection such as differentiation, motility, egress and invasion of cells or tissues. Earlier investigations showed that an acidic environment activates motility of the protozoan parasite T. gondii. Conversely, potassium ions, which are abundant in the intracellular milieu that bathes immotile replicating parasites, suppress motility. Since motility is required for efficient parasite cell invasion and egress we sought to better understand its regulation by environmental cues. We found that low pH stimulates motility by triggering Ca2+-dependent secretion of apical micronemes, and that this cue is sufficient to overcome suppression by potassium ions and drive parasite motility, cell invasion and egress. We also discovered that acidification promotes membrane binding and cytolytic activity of perforin-like protein 1 (PLP1), a pore-forming protein required for efficient egress. Agents that neutralize pH reduce the efficiency of PLP1-dependent perforation of host membranes and compromise egress. Finally, although low pH stimulation of microneme secretion promotes cell invasion, it also causes PLP1-dependent damage to host cells, suggesting a mechanism by which neutral extracellular pH subdues PLP1 activity to allow cell invasion without overt damage to the target cell. These findings implicate acidification as a signal to activate microneme secretion and confine cytolytic activity to egress without compromising the viability of the next cell infected.
Author Summary Toxoplasma and related parasites including those that cause malaria are obligate intracellular pathogens that replicate within a specialized compartment termed the parasitophorous vacuole. To infect new host cells these parasites must first escape from the parasitophorous vacuole and other limiting membranes of the currently infected cell. Escape, or egress as it is often called, depends on the timely release of adhesive proteins and lysis factors from secretory organelles called micronemes. Although this secretory event is crucial for egress, the natural environmental cues that trigger microneme secretion remain poorly defined. Here we discover that acidification of the parasitophorous vacuole is sufficient to trigger microneme secretion and promote the activity of a lysis factor called PLP1. We also show that pH-neutralizing drugs inhibit egress and provide evidence of parasitophorous vacuole acidification approximately coinciding with parasite egress from infected host cells. The findings support a working model in which acidification activates microneme dependent motility and lytic activity to execute egress and destruction of infected cells. The results also provide insight into how PLP1 lytic activity is stimulated during egress in an acidic environment and subsequently suppressed by the neutral extracellular environment, thus permitting cell invasion with minimal damage to the next target cell.
Databáze: OpenAIRE
Externí odkaz: