Oxidative Stress and Pathogenesis in Malaria

Abstract

Malaria is a highly inflammatory and oxidative disease. The production of reactive oxygen species by host phagocytes is an essential component of the host response to Plasmodium infection. Moreover, host oxidative enzymes, such as xanthine oxidase, are upregulated in malaria patients. Although increased production of reactive oxygen species contributes to the clearance of the parasite, excessive amounts of these free radicals can mediate inflammation and cause extensive damage to host cells and tissues, probably contributing to severe pathologies. Plasmodium has a variety of antioxidant enzymes that allow it to survive amidst this oxidative onslaught. However, parasitic degradation of hemoglobin within the infected red blood cell generates free heme, which is released at the end of the replication cycle, further aggravating the oxidative burden on the host and possibly contributing to the severity of life-threatening malarial complications. Additionally, the highly inflammatory response to malaria contributes to exacerbate the oxidative response. In this review, we discuss host and parasite-derived sources of oxidative stress that may promote severe disease in P. falciparum infection. Therapeutics that restore and maintain oxidative balance in malaria patients may be useful in preventing lethal complications of this disease.

Keywords: Plasmodium falciparum; Plasmodium vivax; cerebral malaria; malaria; oxidation; oxidative stress; pathogenesis; reactive oxygen species.

Figure 1

Oxidative stress during Plasmodium infection. Various sources contribute to the oxidative environment during malaria, including upregulation of host enzymes such as XO, the oxidative burst in macrophages upon phagocytosis of infected erythrocytes, and heme release from hemoglobin degradation in host infected erythrocytes. A balance between levels of anti-oxidants in the human host and the generation of ROS determines the levels of oxidative stress. ROS promote inflammation in malaria, leading to the activation of macrophages and the subsequent release of pro-inflammatory cytokines, such as TNF and IL6 among others, but also inflammasome-dependent IL1-β, where ROS provide priming signal 1 and P. falciparum the activating signal 2.