Investigation of liver infection mechanisms of malaria parasites

疟疾的子孢子是侵入肝脏的形式，通过蚊子叮咬注入皮肤。我们发现，细胞穿越对于子孢子通过宿主真皮迁移到循环中是重要的。这种能力防止了子孢子被吞噬细胞破坏和被宿主真皮中的非吞噬细胞阻止。然后它们有效地靶向于肝细胞，并在其中增殖。然而，到目前为止，介导肝脏特定感染的子孢子分子仍不清楚。我们发现属于疟原虫6-cys结构域蛋白家族的两个蛋白Pbs36p和Pbs36以及另一个新的蛋白Pbs41执行这一功能。这些分子是在感染肝脏的子孢子中特异性产生的。靶基因的破坏几乎消除了哺乳动物宿主中的子孢子感染性。侵袭分析表明，突变的寄生虫即使与肝细胞相遇也不能进行感染，导致肝细胞的持续遍历。这些结果表明，这些蛋白是子孢子识别肝细胞并进行感染所必需的。这一发现可能导致新的抗疟疾策略，以防止肝细胞感染子孢子。

Malarial sporozoites, the liver-invasive forms, are injected into the skin by a mosquito bite. We found that cell traversal is important for sporozoites migrate to the circulation through the host dermis. This ability prevents sporozoite destruction by phagocytes and arrest by nonphagocytic cells in the host dermis. Then they are effectively targeted to hepatocytes and proliferate in them. So far, however, sporozoite molecules that mediate the specific infection of the liver remain unknown. We found that two proteins, Pbs36p and Pbs36, belonging to the plasmodium 6-cys domain protein family, and another novel protein, designated Pbs41, carry out this function. These molecules are specifically produced in liver-infective sporozoites. Target disruption of the respective genes nearly abolished sporozoite infectivity in the mammalian host. Invasion assays revealed that the mutant parasites could not commit to infection, even when they encounter with hepatocytes, resulting in continuous traversal of hepatocytes. These results suggest that these proteins are necessary for sporozoites to recognize hepatocytes and commit to infection. This finding might lead to novel anti-malarial strategies that prevent sporozoite infection of the hepatocyte.