The Role of Extracellular Superoxide Dismutase during Innate Immune Responses against Listeria monocytogenes
Break, Timothy J., The Role of Extracellular Superoxide Dismutase during Innate Immune Responses against Listeria monocytogenes. Doctor of Philosophy (Biomedical Sciences), August, 2013, 153 pp., 32 figures, bibliography, 240 titles.
Reactive oxygen and nitrogen species (ROS/RNS) are integral molecules that mediate tissue damage, protect against invading microorganisms, and allow for downstream signaling events to occur. However, how the regulation of ROS/RNS production impacts the ability of immune cells to function properly and respond to a bacterial infection is not well understood. Extracellular superoxide dismutase (ecSOD) is an anti-oxidant enzyme important for protecting tissues from the damaging effects of superoxide, by converting superoxide into hydrogen peroxide, which can be further detoxified. Our data suggest that ecSOD activity is detrimental during Listeria monocytogenes (LM) infection, using congenic mice with varying levels of ecSOD activity (ecSOD HI, ecSOD WT, and ecSOD KO). EcSOD activity decreases the clearance of LM and host survival during infection. Surprisingly, ecSOD activity enhances the recruitment of neutrophils to the liver both prior to, and during LM infection. This enhanced recruitment appears to occur through increased production of neutrophil-attracting chemokines and protection of the extracellular matrix from damage. However, ecSOD activity decreases the ability of neutrophils to effectively clear LM infection, as depletion of neutrophils in ecSOD HI mice had no effect, or was slightly beneficial for clearance of LM. Furthermore, ecSOD WT and ecSOD KO mice had increased CFUs when neutrophils were depleted. We have found that ecSOD activity increases the recruitment of immature neutrophils to the liver, increases the percentage and number of apoptotic neutrophils in the liver, decreases the ability of liver neutrophils to localize to LM lesions effectively, and decreases the activation status of liver neutrophils during LM infection. These data provide novel evidence for the delicate balance that must be maintained to protect against oxidative stress. EcSOD activity is important for protection of tissues from damage, but dampens the host’s ability to clear infection. The data contained herein open up many doors for future studies to understand the regulation of oxidative stress and the impact of ROS/RNS on the clearance of pathogenic infections.