Abstract
Cell-based screening has become the major compound interrogation strategy in Chagas disease drug discovery. Several different cell lines have been deployed as host cells in screening assays. However, host cell characteristics and host-parasite interactions may play an important role when assessing anti-T. cruzi compound activity, ultimately impacting on hit discovery. To verify this hypothesis, four distinct mammalian cell lines (U2OS, THP-1, Vero and L6) were used as T. cruzi host cells in High Content Screening assays. Rates of infection varied greatly between different host cells. Susceptibility to benznidazole also varied, depending on the host cell and parasite strain. A library of 1,280 compounds was screened against the four different cell lines infected with T. cruzi, resulting in the selection of a total of 82 distinct compounds as hits. From these, only two hits were common to all four cell lines assays (2.4%) and 51 were exclusively selected from a single assay (62.2%). Infected U2OS cells were the most sensitive assay, as 55 compounds in total were identified as hits; infected THP-1 yielded the lowest hit rates, with only 16 hit compounds. Of the selected hits, compound FPL64176 presented selective anti-T. cruzi activity and could serve as a starting point for the discovery of new anti-chagasic drugs.
Highlights
Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the most significant human parasitic infections in Latin America, affecting approximately 7 million people [1]
We have evaluated the impact of different cell lines used as host cells for T. cruzi infection in a standardized high content screening (HCS) assay in the context of small molecule compound library screening
In an attempt to address the impact of the host cell on T. cruzi response to compounds, a previously developed HCS assay [28] was adapted to use four cell lines: U2OS, Vero, L6 and THP-1
Summary
Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the most significant human parasitic infections in Latin America, affecting approximately 7 million people [1]. This insect-borne disease, which can be transmitted congenitally and through blood transfusion and organ transplantation [2] causes more than 5000 deaths annually in the Brazilian territory alone [3] and a recent report suggests this mortality rate might be underestimated [4]. It can be argued that differential compound susceptibility depending on the host cell or tissue type might influence the course of the therapeutic outcome in vivo and it is not known whether T. cruzi has a variable response to drug treatment in different infected tissues in vivo
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