Efeito de ExoU na ativação do fator transcricional Nrf2 e na modulação da expressão de genes citoprotetores da resposta antioxidante durante a infecção por Pseudomonas aeruginosa

Abstract

The opportunistic pathogen Pseudomonas aeruginosa is an important agent of respiratory infections in hospitalized patients. Among the virulence factors of P. aeruginosa, ExoU, a cytotoxin injected into the host cell cytosol via the type III secretion system, is associated with the severity of acute infections and increased bloodstream invasion. Previous studies from our laboratory showed that ExoU induces a potent inflammatory response, with intense neutrophil recruitment to the infection site, as well as the production of reactive oxygen and nitrogen intermediates. The transcriptional factor Nrf2 plays an important role in the response to oxidative stress. In the present work, we evaluated the effect of ExoU on the Nrf2 activation and the antioxidant response, using a murine model of pneumossepsis and cultures of human respiratory epithelial cells. We have shown that ExoU was able to inhibit Nrf2 expression and nuclear translocation during P. aeruginosa infection. Moreover, ExoU reduced the mRNA levels of the Nrf2 cytosolic inhibitor, Keap1, and genes encoding proteins with antioxidant action, GCLC, HO-1 and SOD1. The inhibition of the antioxidant system probably contributes to the extended injury observed in lungs infected by ExoU-producing P. aeruginosa strains since there is not an efficient protection against the damage caused by the reactive oxygen species produced by the cells of the lung parenchyma and the neutrophils recruited to the infectious site. The comprehension of the role of oxidative stress for the evolution of infeccious processes may contribute to the development of novel strategies that will allow a better prognosis for patients with P. aeruginosa pneumonia.