The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence
e0003707 - ? (17)
PLoS Neglected Tropical Diseases
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Trypanosoma cruzi expresses an endoplasmic reticulum (ER) localised ascorbate-dependent peroxidase (TcAPx). The parasite-specific nature of this enzyme has attracted interest from the perspective of targeted chemotherapy. To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if the enzyme is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the two front line Chagas disease drugs benznidazole and nifurtimox. This suggests that increased oxidative stress in the ER does not play a significant role in their mechanism of action. Homozygous knockouts were able to proceed through the entire life-cycle in vitro, although they did exhibit a decreased ability to infect Vero cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real time in the chronic stage of the infection. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism. Therefore, TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in protection against immune responses, and should not be considered as a priority target for drug design.
AuthorsTaylor, MC; Lewis, MD; Fortes-Francisco, A; WILKINSON, SR; Kelly, JM
- College Publications