Inherent Oxidative Stress in the Lewis Rat Is Associated with Resistance to Toxoplasmosis

Abstract

ABSTRACT The course of Toxoplasma gondii infection in rats closely resembles that in humans. However, compared to the Brown Norway (BN) rat, the Lewis (LEW) rat is extremely resistant to T. gondii infection. Thus, we performed RNA sequencing analysis of the LEW rat versus the BN rat, with or without T. gondii infection, in order to unravel molecular factors directing robust and rapid early T. gondii -killing mechanisms in the LEW rat. We found that compared to the uninfected BN rat, the uninfected LEW rat has inherently higher transcript levels of cytochrome enzymes (Cyp2d3, Cyp2d5, and Cybrd1, which catalyze generation of reactive oxygen species [ROS]), with concomitant higher levels of ROS. Interestingly, despite having higher levels of ROS, the LEW rat had lower transcript levels for antioxidant enzymes (lactoperoxidase, microsomal glutathione S -transferase 2 and 3, glutathione S -transferase peroxidase kappa 1, and glutathione peroxidase) than the BN rat, suggesting that the LEW rat maintains cellular oxidative stress that it tolerates. Corroboratively, we found that scavenging of superoxide anion by Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) decreased the refractoriness of LEW rat peritoneal cells to T. gondii infection, resulting in proliferation of parasites in LEW rat peritoneal cells which, in turn, led to augmented cell death in the infected cells. Together, our results indicate that the LEW rat maintains inherent cellular oxidative stress that contributes to resistance to invading T. gondii , and they thus unveil new avenues for developing therapeutic agents targeting induction of host cell oxidative stress as a mechanism for killing T. gondii .