Editorial: CD36: Russian roulette of host and parasites during malaria infection

The characterization of the complex interactions occurring in the tissue during infection with the protozoan parasite Plasmodium is necessary to understand and prevent malaria pathogenesis. One syndrome—ALI/ARDS—has been reported in infections with all 5 of the human Plasmodium species and is associated with an increased risk of death [1]. Although the manifestations of this phenomenon have been described extensively, the underlying mechanisms are not fully elucidated, and therefore, efficient therapeutic interventions have not yet been developed. The host scavenger receptor CD36 is thought to play a central role in malaria-induced ALI/ARDS [2], and the targeting of this molecule has been proposed as an adjunctive therapy for severe malaria [3]. The study by Lagassé et al. [4] in this issue of the Journal of Leukocyte Biology shows why, despite its importance in ALI/ARDS, CD36 may not be a good therapeutic target. Acute lung injuries are believed to be the result of the accumulation of PEs in the pulmonary microcirculation, as it has been observed in patients with Plasmodium falciparum and Plasmodium vivax malaria [1], as well as during experimental malaria infections in mice [5]. This process, called sequestration, is brought about by the binding of parasite molecules present on the surface of PE to host receptors on endothelial cells. The accumulation of parasites in the lungs then leads to vascular obstruction, endothelial activation, and dysfunction, as well as local host inflammatory responses [5] that compromise lung function and contribute to an ARDS. PE can bind to a wide variety of endothelial receptors, among which CD36, a member of the class B scavenger receptor family, has been studied extensively. This molecule can bind many ligands, including LPL and long-chain fatty acids, collagen types I and IV, and TSP, and is involved in key physiologic processes, such as atherosclerosis and lipid metabolism [6]. On the surface of endothelial cells, CD36 acts as a receptor, mediating the antiangiogenic/ proapoptotic signal of TSP-1 [6]. Surface molecules of PE are recognized by CD36, among which PfEMP1, encoded by the var multigene family, is the best described. It has been shown that the type of PfEMP1 molecule and the presence or absence of expression of CD36 on endothelial cells correlate with the ability of P. falciparum-infected erythrocytes to bind endothelial cells from different organs in vitro [7]. Therefore, expression of parasite surface antigens and endothelial CD36 could influence the level of parasite sequestration in each organ. CD36 is also expressed on monocytes and macrophages, where it is an important receptor for mediating nonopsonic phagocytosis of Plasmodium-infected erythrocytes [8]. Upon binding, CD36 clusters around the parasitized red cell and triggers intracellular signaling, resulting in PE uptake [9]. Furthermore, through its interaction with TLR4 and -6, it can promote inflammatory responses. As CD36 is involved in parasite sequestration and phagocytosis, depending on the host cell concerned, the binding of PEs to this receptor can promote Plasmodium survival or its death. Therefore, the exact role of CD36 in malaria pathogenesis is unclear. Furthermore, because ALI is likely to be the result of complex cellular interactions happening in the tissue, the underlying molecular mechanisms are not accessible in patients and cannot be modeled in vitro. Rodent models of malaria, such as Plasmodium berghei, Plasmodium yoelii, and Plasmodium chabaudi, offer an opportunity to circumvent these technical issues and to characterize the role of CD36 in ALI. These parasites have been reported to sequester in the lungs of laboratory mice and induce injuries that share many similarities with human infections [5, 10, 11]. It has been demonstrated, for P. berghei at least, that CD36 is the major receptor responsible for parasite accumulation and tissue damage in the lungs [2, 12]. These findings designated CD36 as a major player of malaria-induced lung injuries and raised the hope that by targeting this molecule, ALI/ARDS could be prevented. In their report in this issue of the Journal of Leukocyte Biology, Lagassé et al. [4] use the P. berghei ANKA model to determine the cellular interactions involved in malaria-induced lung injuries. This rodent model of malaria accumulates in the brain, lungs, and liver of