Inhibition of granzyme B mediated apoptosis by Toxoplasma gondii

Abstract

The intracellular protozoan Toxoplasma gondii induces persistent infections in various hosts and is an important opportunistic pathogen of humans with compromised immune responses. Its ability to induce persistent infection may be partially because the parasite has developed ways to inhibit host cell apoptosis. However, few studies have defined the mechanisms for inhibition in physiologically relevant systems. Although the host mounts a T cell mediated immune response against the parasite, T. gondii is not cleared from the host. Granzyme B, a serine protease, is an important pro-apoptotic component of T cell and natural killer cell mediated apoptosis. In this study, we demonstrate that T. gondii can inhibit granzyme B induced apoptosis. Our findings imply the parasite can directly act on granzyme B and to inhibit its proteolytic activity. Although granzyme B is present in the cytosol of infected cells, the proteolytic cleavage of granzyme B substrates such as caspase-3 or Bid, as well as an exogenous substrate, is decreased in infected cells. Inhibition was seen when target cells were treated with recombinant granzyme B and also when effector cells were used to deliver granzyme B into target cells. This study uncovers a novel method the parasite has developed to evade a major component of the immune response. This may be factor in the development of chronic infection.