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Inhibition of Fas-mediated apoptosis by Trypanosoma cruzi infection
J Nakajima-Shimada1, C Zou, M Takagi
1Department of Parasitology, Juntendo University School of Medicine, Tokyo, Japan.
Abstract:
Trypanosoma cruzi-infected and normal control mammalian cells were subjected to analysis of Fas-mediated apoptosis stimulated by an agonistic anti-Fas monoclonal antibody. The infected cells showed markedly hampered apoptotic changes in nuclear morphology, phosphatidylethanolamine translocation from the inside to the outside of the plasma membrane, and DNA fragmentation into multiples of 180 bp, relative to normal control cells. Upstream of these morphological and biochemical consequences, the caspase-3 activity was elevated by the Fas stimulation in a significantly greater proportion of intact control cells, but at a highly reduced rate of infected cells. The rapid elevation of caspase-8 activity in control, apoptotic cells was completely inhibited in infected cells. In an examination of the specificity of other stimulants, X-ray radiation or chemicals such as hydrogen peroxide, colchicine or etoposide did not cause significant differences in apoptotic rates between control and infected cells; tumor necrosis factor-alpha, however, induced a high rate of apoptosis in control cells, with an extremely lowered rate in infected cells. This study demonstrates, for the first time, that T. cruzi infection inhibits one of the earliest steps of death receptor-mediated apoptosis, an effect that most probably involves the inhibition of caspase-8. Differential apoptotic responses in cells infected with T. cruzi and other intracellular parasites are discussed.
Insights
Trypanosoma cruzi infection significantly hinders Fas-mediated apoptosis in mammalian cells by inhibiting early caspase-8 activation. This parasite interferes with programmed cell death pathways, impacting cellular responses to death receptor signaling.
Area of Science:
- Cell Biology
- Immunology
- Parasitology
Background:
- Apoptosis, or programmed cell death, is crucial for multicellular organisms.
- Fas receptor signaling is a key pathway initiating apoptosis.
- Trypanosoma cruzi is a parasite that causes Chagas disease and can manipulate host cell processes.
Purpose of the Study:
- To investigate the effect of Trypanosoma cruzi infection on Fas-mediated apoptosis in mammalian cells.
- To identify the specific steps and molecular mechanisms inhibited by T. cruzi during apoptosis.
- To compare the apoptotic response of infected cells to various death stimuli.
Main Methods:
- Mammalian cells infected with Trypanosoma cruzi were stimulated with an agonistic anti-Fas antibody.
- Analysis of apoptotic markers including nuclear morphology, phosphatidylethanolamine translocation, and DNA fragmentation.
- Assay of caspase-3 and caspase-8 activity.
- Comparison with cells treated with X-ray radiation, hydrogen peroxide, colchicine, etoposide, and tumor necrosis factor-alpha.
Main Results:
- Trypanosoma cruzi-infected cells exhibited significantly reduced Fas-mediated apoptosis compared to control cells.
- Inhibition of early apoptotic events, including caspase-8 activation, was observed in infected cells.
- While other stimuli showed varied effects, tumor necrosis factor-alpha also induced less apoptosis in infected cells, suggesting a targeted inhibition of death receptor pathways.
Conclusions:
- Trypanosoma cruzi infection inhibits a critical early step in death receptor-mediated apoptosis, likely involving caspase-8.
- This parasite's ability to suppress apoptosis may be a mechanism for immune evasion and host cell survival.
- The findings highlight differential apoptotic responses mediated by T. cruzi compared to other intracellular parasites.