Inhibitory role of toll-like receptors agonists in Plasmodium yoelii liver stage development.

It is well known that innate immune plays an important role in controlling the development of Plasmodium liver stage. However, little is known about the role of toll-like receptors (TLR) signalling in the pre-erythrocytic immunity against Plasmodium. Here, we found that pre-treatment with individual TLR agonist pam3CSK4 (TLR2), poly(I:C) (TLR3), LPS (TLR4) and CpG (TLR9) could decrease significantly the liver malaria parasite load in mice for 58%, 63%, 75% and 88% respectively. Moreover, no parasitaemia was observed within 14 days in CpG group mice challenged with 100 sporozoites. At 24 h prior to CpG injection, administration of gadolinium chloride (GdCl(3)) led to the rebound of liver Plasmodium load through inhibiting selectively Kupffer cells (KC) phagocytosis capacity but failed to neutralize completely CpG-induced immunity against malaria liver stage. Compared with the control, pre-treatment of CpG up-regulated hepatic pro-inflammatory cytokines IL-12, IFN-gamma and TNF-alpha, but down-regulated anti-inflammatory cytokines IL-10 and TGF-beta. Hence, our data demonstrated the inhibitory role of diverse TLR agonists in the Plasmodium development during pre-erythrocytic stage. As the most robust agonist, CpG might inhibit the development of Plasmodium liver stage through regulation of intrahepatic inflammatory cytokines and enhancement of KC cells phagocytosis capacity.