Egress

Our group is also keening interested in understanding mechanisms underlying parasite egress from host cells after replication therein. We have shown that a cytolytic protein (perforin-like protein 1) is crucial for efficient egress and is necessary for lethal infection in experimentally infected mice (1). PLP1 is unusual in its use of two distinct membrane binding domains, one that modulates binding and the other that is crucial for stable membrane association (2). Recent findings suggest that the PLP1 cytolytic protein is activated by low pH to aid in parasite egress and that, conversely, its activity is suppressed during parasite invasion to ensure membrane integrity and proper entry (3). The activity of the cytolytic protein is also dictated by exposure to acidic phospholipids, which act as receptors that dictate the directionality of cytolytic activity for egress. Members of the team are also revealing the contributions of a secreted protease, TLN4, and phospholipase, LCAT, to parasite egress. Together, these studies challenge the previous notion of passive egress and suggest that Toxoplasma escapes from cells by secreting several effector proteins that function to disrupt physical barriers enveloping the parasite.

1. Kafsack, B.F.C., Pena, J.D.O., Coppens, I., Ravindran, S., Boothroyd, J.C., and Carruthers, V.B. (2009) Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells. Science 323;530-533.

2. Roiko, M.S. and Carruthers, V.B. (2013) Functional dissection of Toxoplasma gondii Perforin-Like Protein 1 reveals a dual domain mode of membrane binding for cytolysis and parasite egress. J. Biol. Chem. 288:8712-25.

3. Roiko, M.S., Svezhova, N., Carruthers, V.B. (2014) Acidification activates Toxoplasma gondii motility and egress by enhancing secretion and cytolytic activity. PLoS Pathog10(11): e1004488.