A Fine Balance between Life and Death: Modulation of BCL-2 Family Members by Toxoplasma Gondii

Apoptosis has been shown to serve as a mechanism by which cells infected with viruses, bacteria, or intracellular parasites can be eliminated without eliciting an unwanted inflammatory response. Not surprisingly intracellular pathogens have evolved mechanisms by which to inhibit apoptosis, not only avoiding the elimination of the host cell but also extending its life span. Inhibition of apoptosis by intracellu-lar pathogens is accomplished by affecting the fine balance between pro-and anti-apoptotic factors in the infected cell. One mechanism utilized by various microbes is regulation of the pro-and anti-apoptotic proteins of the BCL-2 family (Carmen and Sinai, 2007; Faherty and Maurelli, 2008; Galluzzi et al., 2008). The BCL-2 family includes the pro-apoptotic proteins BCL-2-associated X protein (BAX) and the BCL-2 antagonist/killer-1 (BAK), which directly participate in the release of Cytochrome C from mitochondria (Youle and Strasser, 2008). Other members of the BCL-2 family (e.g., BAD, BID, BIM) participate in the direct or indirect activation of BAX or BAK, thus having pro-apoptotic effects, while others (e.g., BCL-2 and BCL-XL) inhibit these pore forming proteins, thus acting as anti-apoptotic agents (Youle and Strasser, 2008). In a recent Frontiers in Cellular and Infection Microbiology research article , Carmen and Sinai (2011) show that Toxoplasma gondii, an important patho-genic parasite of humans and other animals , affects the stability of several BCL-2 family proteins via a diversity of proteolytic activities. In order to ensure its survival and successful propagation within an infected host, T. gondii inhibits apoptosis in infected cells. Anti-apoptotic events associated with T. gondii infection include activation of the nuclear factor-κ B (NF-κB) inhibition of phosphoinositide 3-kinase (PI3-K), Cytochrome C release from the mitochon-drion, and direct inhibition of the apop-tosome activity (reviewed in Carmen and Sinai, 2007; Laliberte and Carruthers, 2008). Obstruction of Cytochrome C release in T. gondii infected cells has been reported to correlate with increase of BCL-2 transcript level inhibition of mitochondrial targeting and activation of BAX (Hippe et al., 2009), as well as selective degradation of the pro-apoptotic proteins BAX, BAD, and BID (Goebel et al., 2001; Molestina et al., 2003). Degradation of pro-apoptotic members of the BCL-2 family is also observed with other pathogens such as Chlamydia trachomatis (Dong et al., 2005). To better define the requirements for the T. gondii dependent degradation of BCL-2 family proteins, Carmen and Sinai (2011) have now analyzed the levels of BCL-2 family proteins at varying multiplicities of infection (MOI) and in …