Abstract
Malaria is a highly inflammatory disease caused by the protozoan parasite Plasmodium. During the blood stage of infection, patients exhibit fever with high levels of inflammatory cytokines in their blood. However, when cells of the immune system are incubated with the parasite in vitro, their cytokine response is low. In particular, human primary dendritic cells (DCs) respond to Plasmodium falciparum–infected erythrocytes by upregulating maturation markers and chemokines but lack a substantial cytokine response. Because oxidative stress is a trigger of inflammatory cytokines in malaria and synergizes with P. falciparum to induce IL-1β secretion by macrophages, we assessed whether oxidative stress has an impact on DC maturation and function in response to P. falciparum. Using xanthine oxidase, a reactive oxygen species– (ROS) producing enzyme that is increased during malaria, we observed that exposure to extracellular ROS potentiated DC maturation in response to the parasite. Xanthine oxidase–derived ROS increased parasite-induced cytokine secretion and CD80 surface expression in DCs. This enhanced maturation phenotype boosted the DCs’ ability to prime autologous naive CD4+ T cells, resulting in higher T cell proliferation in vitro. Xanthine oxidase–derived ROS did not have an effect on the cytokines produced by primed T cells. We propose that oxidative stress during malaria contributes to the inflammatory response by enhancing the magnitude of DC and CD4+ T cell responses without changing the quality.
Footnotes
This work was supported by a fellowship within the Postdoctoral Programme of the German Academic Exchange Service (to A.G.) and Training Grant 5T32AI007180 (to M.C.T). This work was also supported in part by a New York University Clinical and Translational Science Award grant (UL1 TR001445) from the National Center for Advancing Translational Sciences, National Institutes of Health.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- DC
- dendritic cell
- iRBC
- infected RBC
- mDC
- myeloid DC
- pDC
- plasmacytoid DC
- RM
- repeated measure
- ROS
- reactive oxygen species
- XO
- xanthine oxidase.
- Received September 23, 2019.
- Accepted October 11, 2019.
- Copyright © 2019 The Authors
This article is distributed under the terms of the CC BY 4.0 Unported license.