Malaria is a highly inflammatory, cytokine-driven disease caused by the parasite Plasmodium. The blood-stage infection induces high fever and a strong inflammatory response that is triggered shortly after the rupture of infected erythrocytes. Despite elevated levels of pro-inflammatory cytokines in malaria patients, Plasmodium falciparum infected RBCs (iRBCs) do not induce a cytokine response in human monocyte-derived macrophages in vitro. This suggests a role for a host factor, absent in our in vitro cultures that may be responsible for promoting an inflammatory response. A hallmark of malaria is oxidative stress, as demonstrated by the elevated levels of lipid peroxidation in the plasma of patients. Oxidative stress is a consequence of prolonged exposure to reactive oxygen species (ROS), which have been described to prompt inflammatory responses in other diseases. In our experiments, we utilize xanthine oxidase (XO), an enzyme upregulated in malaria patients, as a potent source of ROS. We show that extracellular ROS produced by XO promote pro-inflammatory cytokine secretion—IL-1β, TNF, IL-10 and IL-6—in macrophages that is blocked by a specific inhibitor of XO or antioxidants. This implies a specific role for ROS in the macrophage inflammatory immune response. In addition, the combined presence of XO and iRBCs generates synergistic cytokine release of IL-1β and chemokines that may feed back into the inflammatory loop, amplifying the inflammatory response. Furthermore, we demonstrate that the production and release of IL-1β is through the activation of the NLRP3 inflammasome: XO primes macrophages to produce pro-ILβ, and iRBCs induce recruitment of the multi-protein inflammasome complex. These results suggest a role for oxidative stress in the induction of inflammation during malaria and uncover a novel inflammasome sensing mechanism for Plasmodium.
|Commitee:||Cronstein, Bruce, Daily, Johanna, Ernst, Joel, Loke, P'ng|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Parasitology, Immunology|
|Keywords:||Inflammasome, Inflammation, Macrophages, Malaria, Oxidative stress, Plasmodium|
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