Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Leadgene Biomedical, Inc. Tainan, Taiwan.
PLoS Pathog. 2022 Apr 29;18(4):e1010469. doi: 10.1371/journal.ppat.1010469. eCollection 2022 Apr.
Dengue virus (DENV) which infects about 390 million people per year in tropical and subtropical areas manifests various disease symptoms, ranging from fever to life-threatening hemorrhage and even shock. To date, there is still no effective treatment for DENV disease, but only supportive care. DENV nonstructural protein 1 (NS1) has been shown to play a key role in disease pathogenesis. Recent studies have shown that anti-DENV NS1 antibody can provide disease protection by blocking the DENV-induced disruption of endothelial integrity. We previously demonstrated that anti-NS1 monoclonal antibody (mAb) protected mice from all four serotypes of DENV challenge. Here, we generated humanized anti-NS1 mAbs and transferred them to mice after DENV infection. The results showed that DENV-induced prolonged bleeding time and skin hemorrhage were reduced, even several days after DENV challenge. Mechanistic studies showed the ability of humanized anti-NS1 mAbs to inhibit NS1-induced vascular hyperpermeability and to elicit Fcγ-dependent complement-mediated cytolysis as well as antibody-dependent cellular cytotoxicity of cells infected with four serotypes of DENV. These results highlight humanized anti-NS1 mAb as a potential therapeutic agent in DENV infection.
登革热病毒（DENV）每年在热带和亚热带地区感染约 3.9 亿人，表现出各种疾病症状，从发热到危及生命的出血，甚至休克。迄今为止，DENV 病仍然没有有效的治疗方法，只能进行支持性护理。登革热非结构蛋白 1（NS1）已被证明在疾病发病机制中发挥关键作用。最近的研究表明，抗 DENV NS1 抗体可以通过阻断 DENV 诱导的内皮完整性破坏来提供疾病保护。我们之前证明，抗 NS1 单克隆抗体（mAb）可以保护小鼠免受所有四种血清型 DENV 的攻击。在这里，我们产生了人源化的抗 NS1 mAb，并在 DENV 感染后将其转移到小鼠体内。结果表明，DENV 诱导的出血时间延长和皮肤出血减少，甚至在 DENV 攻击后几天也如此。机制研究表明，人源化抗 NS1 mAb 能够抑制 NS1 诱导的血管通透性增加，并引发 Fcγ 依赖性补体介导的细胞溶解以及对四种血清型 DENV 感染细胞的抗体依赖性细胞毒性。这些结果突出了人源化抗 NS1 mAb 作为 DENV 感染的一种潜在治疗剂。
