2025/01/01 by S Jayawardhana · 1 voice
Medicine · #Parasitic Diseases Research and Treatment #Research on Leishmaniasis Studies #Trypanosoma species research and implications
paper · doi:10.17037/pubs.04678076
openalex publication_date 2025/01/01 · openalex created_date 2026/01/21 · openalex updated_date 2026/07/01
Chagas disease, or American trypanosomiasis is a potentially life-threatening disease caused by the parasite Trypanosoma cruzi. Predominantly found in Latin America, where morbidity and mortality have a crippling impact in poorer populations, it is now also progressively becoming a global health concern due to increasing migration. Mainly spreading to humans through the faeces of infected triatomine bugs, transmission can also occur through blood transfusions, organ transplants, congenital transmission and also through contaminated food. T. cruzi follows a complex life cycle that includes both invertebrate vectors and mammalian hosts, during which the parasite undergoes several morphological changes. Chagas disease encompasses three distinct stages: an acute phase, an asymptomatic chronic phase and a symptomatic chronic phase, during which the latter may ultimately result in cardiac or gastrointestinal manifestations. However, due to limited treatment options for the different stages of the disease and challenges in early detection, continued research into drug discovery and public health interventions is essential for controlling and eventually eliminating this neglected tropical disease. Utilising the newly developed and highly sensitive bioluminescent and dual expressing bioluminescent:fluorescent parasite cell lines, we have coupled these advances with that of bioluminescence imaging and fluorescent microscopy to identify and monitor T. cruzi infections at the different stages of the disease. Murine models were used to identify possible sites of parasite persistence following non-curative benznidazole treatment and to determine the replication status of such persister parasites. Using the T. cruzi C Brener cell line in BALB/c mice, in both the acute and chronic stages, the results show that parasite survival is random, with no organs or tissues identified where parasites were surviving preferentially and from which they could recrudesce. Further to this, during the acute stage, numbers of persisting amastigotes were greatly reduced in all tissue types following treatment, with the majority of infected host cells harbouring just a single amastigote. With benznidazole-induced DNA fragmentation found to be parasite specific, we used the nucleoside analogue 5-ethynyl-2’-deoxyuridine (EdU) labelling assay to evaluate amastigote DNA replication in vivo. Persister parasites were found to be predominantly in a non-replicative state. Similarly, in immunodeficient CB17 SCID mice, the results showed that in cardiac tissue, all persister parasites were non-replicative. We also explored the impact of non-curative treatment on disease pathology. C3H/HeN mice, were infected with the bioluminescent T. cruzi JR strain and administered with long-term, intermittent suppressive posaconazole treatment to evaluate whether cardiac and gastrointestinal pathologies might be alleviated, despite the absence of sterile cure. However, none of the treatment schedules led to long-term improvements in either cardiac or gastrointestinal pathology. Importantly, this indicates that sterile cure should remain the goal of the drug development community.