Abstract
BackgroundThe neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy.Methodology/Principal FindingsTo assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it 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 front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian 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 murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo.Conclusions/SignificanceTcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design.
Highlights
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease
Throughout Latin America, this disease is an important cause of premature death due to heart failure, and it is currently an emerging public health problem in the US, Europe and across the world
The T. cruzi vitamin-C dependent peroxidase (TcAPx) is an anti-oxidant enzyme which is absent from the mammalian host, and has been proposed as a potential drug target
Summary
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease. Treatment of T. cruzi infection is dependent on two drugs first introduced in the 1970s, benznidazole and nifurtimox. Both of these nitroheterocyclic compounds can have toxic side effects and do not consistently result in sterile cure, in adults. A further problem which impacts on the widespread use of benznidazole and nifurtimox is the potential for cross-resistance Both compounds are pro-drugs and are activated within the parasite by the same mitochondrial nitroreductase (TcNTR). The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx) This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy
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