Abstract
Chronic Trypanosoma cruzi infections are typically lifelong, with small numbers of parasites surviving in restricted tissue sites, which include the gastrointestinal tract. There is considerable debate about the replicative status of these persistent parasites and whether there is a role for dormancy in long-term infection. Here, we investigated T. cruzi proliferation in the colon of chronically infected mice using 5-ethynyl-2′deoxyuridine incorporation into DNA to provide ‘snapshots’ of parasite replication status. Highly sensitive imaging of the extremely rare infection foci, at single-cell resolution, revealed that parasites are three times more likely to be in S-phase during the acute stage than during the chronic stage. By implication, chronic infections of the colon are associated with a reduced rate of parasite replication. Despite this, very few host cells survived infection for more than 14 days, suggesting that T. cruzi persistence continues to involve regular cycles of replication, host cell lysis and re-infection. We could find no evidence for wide-spread dormancy in parasites that persist in this tissue reservoir.
Highlights
Disease latency, mediated by a wide range of mechanisms, is a common feature of viral, bacterial and parasitic infections [1,2,3]
We sought to explore parasite replication by using CellTrace Violet (CTV), a tracker dye that has been employed as a marker for spontaneous dormancy in T. cruzi amastigotes [13]
The report that T. cruzi can undergo a form of spontaneous dormancy has highlighted the possibility that the proliferation status of the parasite could have a role in long-term persistence and contribute to the high rate of treatment failure [13]
Summary
Disease latency, mediated by a wide range of mechanisms, is a common feature of viral, bacterial and parasitic infections [1,2,3]. The terms ‘persistent’, ‘dormant’ and ‘metabolically quiescent’ are used, often interchangeably, to describe pathogens in this state. The phenomenon has evolved independently and frequently in different pathogen groups, presumably because it acts to enhance survival and transmission. The ‘persister’ phenotype does not involve the acquisition of selected mutations, and is often associated with treatment failure, antibiotic tolerance being the best studied example [4,5]. In the case of Chagas disease, some form of dormancy or restricted replication has been widely postulated as a mechanism that might explain long-term parasite survival and the high rate of treatment failure [6]
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