Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Infect Immun. 2011 Sep;79(9):3633-41. doi: 10.1128/IAI.05459-11. Epub 2011 Jun 27.
Malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be "clinically and diagnostically silent." Merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. How the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. Likewise, how the initial liver stages may shape responses to blood-stage parasites is unknown. Here, using both sporozoite- and blood-stage-induced infections with the rodent malaria parasite Plasmodium berghei ANKA, we show that the MyD88 and Toll-like receptor 2/4 (TLR2/4) pathways play critical roles in the development of experimental cerebral malaria (ECM). Strikingly, an absolute dependence on MyD88 and TLR2/4 was observed when infections were initiated with sporozoites. In addition, we show that caspase-1 activation of interleukin-1β (IL-1β) and IL-18, which is associated with the inflammasome pathway, does not contribute to P. berghei ANKA-induced immunopathology. Consistent with these data, prophylactic cover with the IL-1β antagonist anakinra did not reduce the incidence of ECM. Therefore, we propose that protection against ECM due to loss of TLR signaling functions is caused by effector mechanisms other than IL-1β activation.
疟原虫感染是由子孢子入侵肝细胞和肝期无性繁殖引发的，这些过程被认为是“临床和诊断上无声无息的”。从肝细胞逸出的裂殖子周期性地感染红细胞并引起疾病。宿主固有免疫系统如何影响疾病结局以及在疟疾期间诱导效应细胞仍不清楚。同样，初始肝期如何影响对血期寄生虫的反应也是未知的。在这里，我们使用啮齿动物疟原虫 Plasmodium berghei ANKA 的子孢子和血期诱导感染，表明 MyD88 和 Toll 样受体 2/4（TLR2/4）途径在实验性脑型疟疾（ECM）的发展中起关键作用。引人注目的是，当用子孢子起始感染时，观察到对 MyD88 和 TLR2/4 的绝对依赖性。此外，我们表明，半胱天冬酶-1 激活白细胞介素-1β（IL-1β）和 IL-18，与炎症小体途径相关，并不导致 P. berghei ANKA 诱导的免疫病理学。与这些数据一致，预防性使用 IL-1β拮抗剂 anakinra 并不能降低 ECM 的发生率。因此，我们提出由于 TLR 信号转导功能的丧失而导致对 ECM 的保护是由 IL-1β 激活以外的效应机制引起的。
