Roles Of Human ApoE Isoforms In Host Immune Response And Pathogenesis With Infection Of Plasmodium Berghei ANKA

Malaria is still one of the most serious global infectious diseases that endanger human health.Cerebral malaria(CM)is a severe disease that develops mostly from infection of Plasmodium falciparum and can cause serious damages to the host.The mechanism of the occurrence of cerebral malaria is not completely understood.One of the hypothesis is that red blood cells infected with malaria parasite clog the capillaries of the host brain,which can cause oxygen deficiency and excessive inflammatory response.Some allelic types of apolipoprotein E(ApoE)proteins have been associated with cerebral malaria.Studies have shown that median parasite densities were significantly higher in ApoE4 children compared to non-ApoE4 children.In this study,we infected transgenic mice(ApoE gene targeted replacement)that specifically expressed different types of human ApoE proteins with P.berghei ANKA to investigate the protective effects of ApoE proteins.Disease phenotypes,pathological changes in the brain,and cytokine levels of transgenic mice were measured after infection with the parasite.No significant changes were observed between ApoE3,ApoE4,and wild type(WT)mice after infection.However,ApoE2 transgenic mice showed more resistance to cerebral malaria.Further analysis showed that there was no difference in cholesterol content in the brains between WT and the transgenic mice,excluding the hypothesis that ApoE protein influences malaria infection by regulating cholesterol levels.Compared with other genotypes,the ApoE2 transgenic mice had fewer pathological changes and produced higher levels of inflammatory cytokines than the WT mice day2 post-infection.At day 5 post-infection,ApoE2 transgenic mice up-regulated expression of IL-10,suggesting a down-regulation of inflammatory response.These results indicate that in the early stages of the parasite infection,ApoE2 transgenic mice can quickly mobilize inflammatory responses against the parasites,and by the late infection,produce IL-10 to protect the host from dying of excessive inflammatory reaction.Our results show that different ApoE transgenic mice have different responses to malaria infection.ApoE2 can provide protection against experimental cerebral malaria,which may offer new ideas for prevention and control of malaria.