Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
mBio. 2018 Nov 20;9(6):e02194-18. doi: 10.1128/mBio.02194-18.
sporozoites are injected into the skin as mosquitoes probe for blood. From here, they migrate through the dermis to find blood vessels which they enter in order to be rapidly carried to the liver, where they invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic stage. Once sporozoites enter the blood circulation, they are found in hepatocytes within minutes. In contrast, sporozoite exit from the inoculation site resembles a slow trickle and occurs over several hours. Thus, sporozoites spend the majority of their extracellular time at the inoculation site, raising the hypothesis that this is when the malarial parasite is most vulnerable to antibody-mediated destruction. Here, we investigate this hypothesis and demonstrate that the neutralizing capacity of circulating antibodies is greater at the inoculation site than in the blood circulation. Furthermore, these antibodies are working, at least in part, by impacting sporozoite motility at the inoculation site. Using actively and passively immunized mice, we found that most parasites are either immobilized at the site of injection or display reduced motility, particularly in their net displacement. We also found that antibodies severely impair the entry of sporozoites into the bloodstream. Overall, our data suggest that antibodies targeting the migratory sporozoite exert a large proportion of their protective effect at the inoculation site. Studies in experimental animal models and humans have shown that antibodies against sporozoites abolish parasite infectivity and provide sterile immunity. While it is well documented that these antibodies can be induced after immunization with attenuated parasites or subunit vaccines, the mechanisms by and location in which they neutralize parasites have not been fully elucidated. Here, we report studies indicating that these antibodies display a significant portion of their protective effect in the skin after injection of sporozoites and that one mechanism by which they work is by impairing sporozoite motility, thus diminishing their ability to reach blood vessels. These results suggest that immune protection against malaria begins at the earliest stages of parasite infection and emphasize the need of performing parasite challenge in the skin for the evaluation of protective immunity.
疟原虫子孢子随着蚊子的叮咬进入皮肤。然后，它们穿过真皮层，寻找血管，进入血管后迅速被输送到肝脏，在那里它们侵入肝细胞并发育为下一个生命周期阶段，即红细胞外期。一旦子孢子进入血液循环，它们在几分钟内就能在肝细胞中被发现。相比之下，子孢子从接种部位的逸出类似于缓慢的涓涓细流，需要几个小时才能完成。因此，子孢子在接种部位的大部分时间都处于细胞外状态，这就提出了一个假说，即疟原虫在这个时候最容易受到抗体介导的破坏。在这里，我们研究了这个假说，并证明了循环抗体的中和能力在接种部位比在血液循环中更强。此外，这些抗体至少部分通过影响接种部位的子孢子运动起作用。通过主动和被动免疫的小鼠，我们发现大多数寄生虫要么在注射部位被固定，要么运动能力降低，特别是在它们的净位移方面。我们还发现，抗体严重损害了子孢子进入血液的能力。总的来说，我们的数据表明，针对迁移性子孢子的抗体在接种部位发挥了其大部分保护作用。实验动物模型和人类的研究表明，针对子孢子的抗体可消除寄生虫的感染力并提供无菌免疫力。虽然已经有文献证明，用减毒寄生虫或亚单位疫苗免疫可以诱导这些抗体，但它们中和寄生虫的机制和位置尚未完全阐明。在这里，我们报告的研究表明，这些抗体在注射子孢子后在皮肤中显示出显著的保护作用，它们的工作机制之一是损害子孢子的运动能力，从而降低其到达血管的能力。这些结果表明，针对疟疾的免疫保护始于寄生虫感染的最早阶段，并强调了在皮肤中进行寄生虫挑战以评估保护性免疫的必要性。
