Malaria is a deadly infectious disease caused by the intraerythrocytic protozoan parasite Plasmodium. The four species of Plasmodium known to affect humans all produce an inorganic crystal called hemozoin (HZ) during the heme detoxification process. HZ is released from the food vacuole into circulation during erythrocyte lysis, while the released parasites further infect additional naive red blood cells. Once in circulation, HZ is rapidly taken up by circulating monocytes and tissue macrophages, inducing the production of pro-inflammatory mediators, such as interleukin-1β (IL-1β). Over the last few years, it has been reported that HZ, similar to uric acid crystals, asbestos, and silica, is able to trigger IL-1β production via the activation of the NOD-like receptor containing pyrin domain 3 (NLRP3) inflammasome complex. Additionally, recent findings have shown that host factors, such as fibrinogen, have the ability to adhere to free HZ and modify its capacity to activate host immune cells. Although much has been discovered regarding NLRP3 inflammasome induction, the mechanism through which this intracellular multimolecular complex is activated remains unclear. In the present review, the most recent discoveries regarding the capacity of HZ to trigger this innate immune complex as well as the impact of HZ on several other inflammatory signaling pathways will be discussed.

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Malaria is one of the most prevalent infectious diseases worldwide with more than 250 million cases and one million deaths each year. One of the well-characterized malarial-related molecules is hemozoin (HZ), which is a dark-brown crystal formed by the parasite and released into the host during the burst of infected red blood cells. HZ has a stimulatory effect on the host immune system such as its ability to induce pro-inflammatory mediators responsible for some of the malaria related clinical symptoms such as fever. However, the host serum proteins interacting with malarial HZ as well as how this interaction modifies its recognition by phagocytes remained elusive. In the actual study, using proteomic liquid chromatographic mass spectrometry (LC-MS/MS) and immunochemical approaches, we compared the serum protein profiles of malaria patients and healthy individuals. Particularly, we utilized the malarial HZ itself to capture serum proteins capable to bind to HZ, enabling us to identify several proteins such as apolipoprotein E (ApoE), serum amyloid A (SAA), gelsolin, complement factor H and fibrinogen that were found to differ among healthy and malaria individual. Of particular interest is LPS binding protein (LBP), which is reported herein for the first time in the context of malaria. LBP is usually produced during innate inflammatory response to gram-negative bacterial infections. The exact role of these biomarkers and acute phase responses in malaria in general and HZ in particular remains to be investigated. The identification of these inflammation-related biomarkers in malaria paves the way to potentially utilize them as diagnostic and therapeutic targets.

Cerebral malaria claims the life of millions of people each year, particularly those of children, and is a major global public health problem. Thus, the identification of novel malaria biomarkers that could be utilized as diagnostic or therapeutic targets is becoming increasingly important. Using a proteomic approach, we previously identified unique biomarkers in the sera of malaria-infected individuals, including apolipoprotein E (ApoE). ApoE is the dominant apolipoprotein in the brain and has been implicated in several neurological disorders; therefore, we were interested in the potential role of ApoE in cerebral malaria. Here we report the first demonstration that cerebral malaria is markedly attenuated in ApoE−/− mice. The protection provided by the absence of ApoE was associated with decreased sequestration of parasites and T cells within the brain, and was determined to be independent from the involvement of ApoE receptors and from the altered lipid metabolism associated with the knock-out mice. Importantly, we demonstrated that treatment of mice with the ApoE antagonist heparin octasaccharide significantly decreased the incidence of cerebral malaria. Overall, our study indicates that the reduction of ApoE could be utilized in the development of therapeutic treatments aimed at mitigating the neuropathology of cerebral malaria.