NA damage and oxidative stress in human cells infected by Trypanosoma cruz

Autor(es)

Florentino, V, Pilar T. ; Mendes, Davi ^[1] ; Vitorino, Francisca Nathalia L. ^[2] ; Martins, Davi J. ^[1] ; Cunha, Julia P. C. ^[2] ; Mortara, Renato A. ^[3] ; Menck, Carlos F. M. ^[1]

Afiliação do(s) autor(es)

^[1] Florentino, Pilar T., V, Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo - Brazil

^[2] Butantan Inst, Special Lab Cell Cycle, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 17, n. 4 APR 2021.
• Citações Web of Science: 4

Resumo

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 gamma H2Ax, 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. Author summary Chagas disease is a neglected disease that afflicts over eight million individuals worldwide. Oxidative stress is an important cell response when infected by Trypanosoma cruzi, etiologic agent of Chagas disease, although its role in host cell DNA/RNA metabolism has not been fully described. In this study, we investigated how T. cruzi infection and oxidative stress affect DNA molecule and the host cell metabolism. Data show that T. cruzi infection promote oxidative stress, which induce protein oxidation and DNA damage in human cells. Interestingly, control of the oxidative stress reduces the parasite capacity of infection. Until now, drug treatment with Nifurtimox or Benznidazole (BNZ) is only effective in the acute phase of the disease. This work revealed that pre administered BNZ to the host cells was also efficient in reducing oxidative stress and DNA damage, caused by parasite infection. Therefore, BNZ could be preparing cellular metabolism to respond to T. cruzi infection also by controlling the oxidative stress that may be necessary for the parasite propagation. (AU)

• Processo FAPESP: 19/19435-3 - Papel de danos no DNA e função mitocondrial em envelhecimento vascular, imune e neurológico (DNA MoVINg)
• Beneficiário: Carlos Frederico Martins Menck
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/01760-0 - Investigação do envolvimento de lesões no genoma e seu reparo em células infectadas por Trypanosoma cruzi
• Beneficiário: Pilar Sampaio Tavares Veras
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado