DNA damage and oxidative stress in human cells infected by Trypanosoma cruzi

Abstract

Trypanosoma cruzi is the etiologic agent of Chagas’ disease. Infected cells with T. cruzi activate several responses that promote unbalance of reactive oxygen species (ROS) that may cause DNA damage that activate cellular responses including DNA repair processes. In this work, HeLa cells and AC16 human cardiomyocyte cell line were infected with T. cruzi to investigate host cell responses at genome level during parasites intracellular life cycle. In fact, alkaline sensitive sites and oxidized DNA bases were detected in the host cell genetic material particularly in early stages of infection. These DNA lesions were accompanied by phosphorylation of the histone H2Ax, inducing γH2Ax, a marker of genotoxic stress. Moreover, Poly [ADP-ribose] polymerase) and 8-oxoguanine glycosylase (OGG1) are recruited to host cell nuclei, indicating activation of the DNA repair process. In infected cells, chromatin-associated proteins are carbonylated, as a possible consequence of oxidative stress and the nuclear factor erythroid 2–related factor 2 (NRF2) is induced early after infection, suggesting that the host cell antioxidant defenses are activated. However, at late stages of infection, NRF2 is downregulated. Interestingly, host cells pretreated with glutathione precursor, N-acetyl cysteine, NRF2 activator (Sulforaphane), and also Benznidonazol (BNZ) reduce parasite burst significantly, and DNA damage. These data indicate that the balance of oxidative stress and DNA damage induction in host cells may play a role during the process of infection itself, and interference in these processes may hamper T. cruzi infection, revealing potential target pathways for the therapy support.

Modulation of the Host Nuclear Compartment by Trypanosoma cruzi Uncovers Effects on Host Transcription and Splicing Machinery

“…The inhibition should affect especially the transcriptional elongation and splicing activity ( Rodriguez et al., 2007 ). Recent data reinforce our hypothesis showing a significant reduction in the newly transcripts synthesis during T. cruzi infection ( Florentino et al., 2021 ).…”

Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy

“…The production of ROS in infected cells is understood as an active response to parasite elimination, but with the consequence of generating damage to the myocardium as shown in animal models of CCC ( Paiva et al., 2018 ) and also favoring the parasite’s survival and causing DNA damage to the host ( Florentino et al., 2021 ). In CCC hiPSC-CM, the activation of the mTORC1 pathways indicates that ROS response is the main strategy for these cells to avoid T. cruzi proliferation but with consequences to the correct function to the translational machinery of the cell, leading to the activation of ER-stress response and consequent apoptosis, generating an unfavorable scenario for the functioning and survival of the cell.…”

Genetic Instability among Hitnü People Living in Colombian Crude-Oil Exploitation Areas

“…To the best of our knowledge, this is the first time that this protective association has been reported, so more in-depth studies are required to confirm these results and elucidate the biological mechanisms involved. This hypothesis is based on the following considerations: (1) T. cruzi infection generally involves increased Ca 2+ influx [ 39 ] and exacerbated production of reactive oxygen species (ROS) in host cells [ 40 ]; and (2) the ROS released in response to T. cruzi infection cause DNA damage, such as 8-oxodeoxydeoxyguanine (8-oxodG) lesions and DNA strand breaks, which signal poly ADP-ribosylation of proteins (PARylation) [ 41 ]. Thus, in a state of chronic, untreated infection and a permanent state of exacerbated ROS production, it is possible that the host cell deploys mechanisms to cope with and overcome this state, including the expression of antioxidant enzymes, specific cofactors, and efficient repair pathways.…”