Innate inflammatory and phagocytic responses to Plasmodium falciparum: linked processes or molecularly discrete pathways?s

Abstract

Background: Effective innate immune responses are important for control of malaria blood-stage infection and in preventing progression to severe malaria in non-immune individuals. Key innate defenses include a tightly regulated inflammatory response and host clearance of parasitized erythrocytes (PE). Pattern recognition receptors on macrophages mediate these processes: parasite glycosylphosphatidylinositol (GPI) activates TLR2 to induce inflammation – an excess of which is associated with severe malaria – while scavenger receptor CD36 mediates non-opsonic uptake of PEs. Both pathways are potential therapeutic targets, but it is unclear whether they are interdependent. Findings in other systems implicate CD36 in inflammation and TLR2 in phagocytosis, and recent evidence indicates that CD36 and TLR2 can directly cooperate. 
 Methods: We investigated whether the innate inflammatory and phagocytic responses of macrophages to P. falciparum are separable: does CD36-mediated PE internalization have inflammatory outcomes, and does TLR2 regulate PE uptake? CD36-mediated endocytosis failed to induce TNFα production. As a more representative model of innate PE uptake, α-CD36 EBABs (Erythrocyte-Biotin-Avidin-Biotinylated antibody) were generated; macrophages internalized EBABs in a CD36-specific manner via a signaling pathway similar to that of PE uptake. 
 Results: Compared to controls, neither PE nor EBAB internalization induced TNFα release, indicating that the inflammatory consequences of CD36 engagement are ligand dependent. Regarding TLR2 regulation of PE uptake, wild type and Tlr2-/- macrophages showed no differences in EBAB or PE uptake. Pre-treatment of macrophages with P. falciparum GPI enhanced EBAB internalization, but this effect was CD36-independent and generalizable to other TLR ligands. 
 Conclusions: These results suggest that innate inflammatory and phagocytic responses of macrophages to malaria are discrete. Thus, therapeutic augmentation of CD36-mediated PE uptake should not exacerbate inflammation, nor should inhibition of the TLR2 pathway compromise CD36-mediated PE clearance. The role of TLR-enhanced internalization in malaria will be further examined.