Apoptosis and its modulation during infection with Toxoplasma gondii: molecular mechanisms and role in pathogenesis.
Infection with the obligate intracellular protozoan Toxoplasma gondii leads to lifelong persistence of the parasite in its mammalian hosts including humans. Apoptosis plays crucial roles in the interaction between the host and the parasite. This includes innate and adaptive defense mechanisms to restrict intracellular parasite replication as well as regulatory functions to modulate the host's immune response. Not surprisingly, however, T. gondii also extensively modifies apoptosis of its own host cell or of uninfected bystander cells. After infection, apoptosis is triggered in T lymphocytes and other leukocytes, thereby leading to suppressed immune responses to the parasite. T cell apoptosis may be largely mediated by Fas engagement but also occurs independently of Fas under certain conditions. Depending on the magnitude of T cell apoptosis, it is either associated with unrestricted parasite replication and severe pathology or facilitates a stable parasite-host-interaction. However, T. gondii has also evolved strategies to inhibit host cell apoptosis. Apoptosis is blocked by indirect mechanisms in uninfected bystander cells, thereby modulating the inflammatory response to the parasite. In contrast, inhibition of apoptosis in infected host cells by direct interference with apoptosis-signaling cascades is thought to facilitate the intracellular development of T. gondii. Blockade of apoptosis by intracellular parasites may be achieved by different means including interference with the caspase cascade, increased expression of antiapoptotic molecules by infected host cells, and a decreased activity of the poly(ADP-ribose) polymerase. The intriguing dual activity of T. gondii to both promote and inhibit apoptosis requires a tight regulation to promote a stable parasite host-interaction and establishment of persistent toxoplasmosis.
Lüder
C G K
CG
Institute of Medical Microbiology, Georg-August-University, Kreuzbergring 57, 37075 Göttingen, Germany. clueder@gwdg.de
Gross
U
U
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D014122:Toxoplasma / Q000502:physiology*; D014123:Toxoplasmosis / Q000469:parasitology / Q000473:pathology*