Fas/CD95-Mediated Apoptosis of Type II Cells Is Blocked byToxoplasma gondiiPrimarily via Interference with the Mitochondrial Amplification Loop

Abstract

The intracellular protozoan Toxoplasma gondii induces persistent infections in various hosts and is an important opportunistic pathogen of humans with immature or deficient immune responses. The ability to survive intracellularly largely depends on the blocking of different proapoptotic signaling cascades of its host cell. Fas/CD95 triggers an apoptotic cascade that is crucial for immunity and the outcome of infectious diseases. We have determined the mechanism by which T. gondii counteracts death receptor-mediated cell death in type II cells that transduce Fas/CD95 ligation via caspase 8-mediated activation of the mitochondrial amplification loop. The results showed that infection with T. gondii significantly reduced Fas/CD95-triggered apoptosis in HeLa cells by inhibiting the activities of initiator caspases 8 and 9 and effector caspase 3/7. Parasitic infection dose dependently diminished cleavage of caspase 8, the BH3-only protein Bid, and the downstream caspases 9 and 3. Importantly, interference with Fas/CD95-triggered caspase 8 and caspase 3/7 activities after parasitic infection was largely dependent on the presence of caspase 9. Within the mitochondrial amplification loop, T. gondii significantly inhibited the Fas/CD95-triggered release of cytochrome c into the host cell cytosol. These results indicate that T. gondii inhibits Fas/CD95-mediated apoptosis in type II cells primarily by decreasing the apoptogenic function of mitochondria.

Toxoplasma gondiiinfection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax

“…T. gondii actively invades a wide range of host cells and subverts major cellular functions in its host (Plattner and Soldati-Favre, 2008), including apoptotic signalling (Lüder et al, 2009). Infection with T. gondii renders host cells resistant to a variety of pro-apoptotic signals (Nash et al, 1998;Goebel et al, 1999;Goebel et al, 2001;Molestina et al, 2003;Carmen et al, 2006;Vutova et al, 2007;Hippe et al, 2008) and might also counteract the innate 'suicide' program of parasite-infected cells (Lüder and Gross, 2005).…”

A Review: Competence, Compromise, and Concomitance—Reaction of the Host Cell To Toxoplasma gondii Infection and Development

“…In type I host cells (like SKW6.4 cells), T. gondii blocks this apoptotic cascade directly through interference with caspase 8. In type II host cells (like HeLa cells), T. gondii significantly reduces Fas/ CD95-triggered apoptosis by inhibiting the activities of initiator caspases 8 and 9 and effector caspase 3/7, by decreasing the apoptogenic function of mitochondria at the mitochondrial amplification loop (Vutova et al, 2007;Hippe et al, 2008).…”

“…4, AUGUST 2011 cells is an anti-apoptosis-induced reaction triggered by T. gondii infection. Interference of T. gondii with host cell apoptosis is related to virulence factors of T. gondii strains (Angeloni et al, 2009) and depends on the cell types being infected (Vutova et al, 2007;Hippe et al, 2008). The mechanisms are mainly through regulating the death receptor (Hippe et al, 2008) and the NF-kB and the PI3K pathways (Yang et al, 2004).…”

“…Interference of T. gondii with host cell apoptosis is related to virulence factors of T. gondii strains (Angeloni et al, 2009) and depends on the cell types being infected (Vutova et al, 2007;Hippe et al, 2008). The mechanisms are mainly through regulating the death receptor (Hippe et al, 2008) and the NF-kB and the PI3K pathways (Yang et al, 2004). Toxoplasma gondii inhibits death receptor-mediated apoptosis in host cells (Goebel et al, 2001;Payne et al, 2003;Vutova et al, 2007).…”

“…The cells infected by T. gondii are resistant to multiple inducers of apoptosis, including cytotoxic T lymphocyte (Fas-dependent or -independent), IL-2 deprivation, gamma irradiation, UV irradiation, and the calcium ionophore beauvericin (Nash et al, 1998;Luder and Gross, 2005). However, T. gondii blocks host cell apoptosis, including the inhibition of cytochrome C released from host cell mitochondria, upregulation of anti-apoptotic proteins of the Bcl-2 and IAP families, interference with proapoptotic Bax and Bad, modulation of cell death-regulating kinase activities, inhibition of caspase, and possibly modulation of cytochrome Cinduced caspase 3/7 activation (Hippe et al, 2008).…”