Drug transporter and oxidative stress gene expression in human macrophages infected with benznidazole-sensitive and naturally benznidazole-resistant Trypanosoma cruzi parasites treated with benznidazole

Chagas disease is a potentially life-threatening disease caused by the protozoan parasite Trypanosoma cruzi. Current therapeutic management is limited to treatment with nitroheterocyclic drugs, such as nifurtimox (NFX) and benznidazole (BZ). Thus, the identification of affordable and readily available drugs to treat resistant parasites is urgently required worldwide. To analyse the effects of BZ on human macrophage gene expression, a quantitative PCR (qPCR) array analysis was performed using drug transporter and oxidative stress pathway genes to compare the gene expression profiles of human differentiated THP-1 macrophage (THP-1 MΦ) cells infected or not with benznidazole-sensitive (CL Brener) and naturally benznidazole-resistant (Colombiana) T. cruzi parasites followed by treatment with BZ. The gene expression analysis indicated that the expression levels of 62 genes were either up- or downregulated at least 3-fold in the host upon infection with CL Brener and BZ treatment, of which 46 were upregulated and 16 were downregulated. Moreover, the expression level of 32 genes was altered in THP-1 MФ cells infected with Colombiana and treated with BZ, of which 29 were upregulated and 3 were downregulated. Our results revealed that depending on the specific condition, human THP-1 MΦ cells infected with T. cruzi strains with sensitive or resistant phenotypes and treated with BZ expressed high mRNA levels of AQP1, AQP9 and ABCB1 (MDR1) compared to those of the control cells. Our findings suggest that the proteins encoded by AQP1, AQP9 and ABCB1 may be implicated in benznidazole detoxification. Therefore, studies on gene expression are required to better understand the host response to pathogens and drug treatment integrated with functional and metabolic data to identify potentially novel targets for the treatment of this important and neglected tropical disease.