Abstract
The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5–8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.
Highlights
At achieving parasitological cure, showed no significant benefit in patients who had already developed advanced chagasic cardiomyopathy[11]
Using the T. cruzi CL Brener-BALB/c model, we found that chronic infections could be cured with 5 daily oral doses of 100 mg kg−1 benznidazole
Drug efficacy was assessed by both in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression to enhance the reactivation of any residual infection (Methods)
Summary
At achieving parasitological cure, showed no significant benefit in patients who had already developed advanced chagasic cardiomyopathy[11]. To increase the accuracy and reproducibility of drug testing, we developed highly sensitive bioluminescence methodology based on the expression by trypanosomes of a red-shifted luciferase reporter[22,23,24] This in vivo imaging procedure has a limit of detection of 100–1000 parasites, and facilitates the real-time tracking of parasite burden in individual mice during long-term experimental infections. Transient bioluminescent foci can be detected at peripheral sites during chronic infections, which fluctuate in a spatiotemporally dynamic manner, appearing and disappearing over a period of hours This bioluminescence imaging system is more reliable than PCR-based approaches for tracking experimental T. cruzi infections and for confirming parasitological cure[25]. We describe the use of this predictive model to undertake a detailed comparison of the efficacy of the nitroheterocyclic agents benznidazole, nifurtimox, fexinidazole and fexindazole sulfone against acute and chronic T. cruzi infections
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