Abstract
The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial.
Highlights
Chagas disease is a major public health problem in Latin America and is increasingly prevalent in other regions as a result of migration patterns [1, 2]
To streamline the drug discovery process, we sought to improve the utility of current predictive models of experimental Chagas disease by developing an enhanced in vivo imaging system
This in vivo imaging system has a limit of detection of between 100 and 1,000 parasites and has allowed parasite burden to be assessed in real time during experimental chronic infections in individual mice [24]
Summary
Chagas disease is a major public health problem in Latin America and is increasingly prevalent in other regions as a result of migration patterns [1, 2]. Benznidazole and nifurtimox are prodrugs and both are activated within T. cruzi by the same mitochondrial nitroreductase (TcNTR) [8], leading to the generation of reactive metabolites which mediate parasite killing [9,10,11] This shared activation mechanism provides potential for cross-resistance [8, 12, 13] and highlights the need to identify additional therapeutic agents which target distinct biochemical pathways. In T. cruzi, the bioluminescent reporter is expressed at similar levels in different parasite life cycle stages, has no effect on growth properties or virulence, and is maintained at constant levels for more than 12 months in the absence of selective drug pressure This in vivo imaging system has a limit of detection of between 100 and 1,000 parasites and has allowed parasite burden to be assessed in real time during experimental chronic infections in individual mice [24]. In line with a recent clinical trial, our predictive model suggests major limitations in the utility of this drug
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