Institut Pasteur, Université Paris Cité, Malaria Infection and Immunity, BioSPC, F-75015, Paris, France.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Cell Rep. 2023 Jul 25;42(7):112681. doi: 10.1016/j.celrep.2023.112681. Epub 2023 Jun 28.
Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.
人类针对疟原虫裂殖子表面环子孢子蛋白（PfCSP）的单克隆抗体（hmAbs）是预防疟疾感染的有前途的工具。然而，其保护机制仍不清楚。在这里，我们使用 13 种独特的 PfCSP hmAbs，全面了解 PfCSP hmAbs 如何中和宿主组织中的孢子。在皮肤中，孢子对 hmAb 介导的中和最敏感。然而，罕见但有效的 hmAbs 还可以中和血液和肝脏中的孢子。在组织中的有效保护主要与高亲和力和高细胞毒性 hmAbs 相关，这些 hmAbs 在没有补体和宿主细胞的情况下诱导寄生虫在体外迅速丧失适应性。3D 基质测定极大地增强了 hmAb 的细胞毒性，并模拟了皮肤依赖性保护，表明对运动的孢子施加的物理应激对于展开 hmAb 的保护潜力至关重要。因此，这种功能性 3D 细胞毒性测定可用于筛选有效的抗 PfCSP hmAbs 和疫苗。
