Laboratorio de Investigaciones Infectológicas y Biología Molecular, Infectología, Departamento de Medicina, Hospital de Niños Dr. Ricardo Gutiérrez, Gallo 1330, Buenos Aires 1425, Argentina; Fundación INFANT, Gavilán 94, Buenos Aires 1406, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Godoy Cruz 2290, Buenos Aires 1425, Argentina.
Laboratorio de Investigaciones Infectológicas y Biología Molecular, Infectología, Departamento de Medicina, Hospital de Niños Dr. Ricardo Gutiérrez, Gallo 1330, Buenos Aires 1425, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Intendente Güiraldes 2160, Buenos Aires 1428, Argentina.
Microbes Infect. 2024 Nov-Dec;26(8):105378. doi: 10.1016/j.micinf.2024.105378. Epub 2024 Jun 14.
Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is one of the mechanisms contributing to increased severity during heterotypic, secondary infection. The complement protein C1q has been shown to reduce the magnitude of ADE in vitro. Therefore, we investigated the mechanisms of C1q modulation of ADE, focusing on processes of viral entry. Using a model of ADE of DENV-1 infection in human myeloid cell lines in the presence of monoclonal antibodies, 4G2 and 2H2, we found that C1q produced nearly a 40-fold reduction of ADE of DENV-1 in K562 cells, but had no effect in U937 cells. In K562 cells, C1q reduced adsorption of DENV-1/4G2 and exerted a dual inhibitory effect on adsorption and internalization of DENV-1/2H2. Distinct endocytic pathways in the presence of antibody corresponded to conditions where C1q produced a differential action. Also, C1q did not affect the intrinsic cell response mediated by FcγR in human myeloid cells. The modulation of ADE of DENV-1 by C1q is dependent on the FcγR expressed on immune cells and the specificity of the antibody comprising the immune complex. Understanding protective and pathogenic mechanisms in the humoral response to DENV infections is crucial for the successful design of antivirals and vaccines.
抗体依赖的增强（ADE）作用是导致登革病毒（DENV）感染异型、二次感染时病情加重的机制之一。补体蛋白 C1q 已被证明可降低体外 ADE 的程度。因此，我们研究了 C1q 调节 ADE 的机制，重点关注病毒进入的过程。在存在单克隆抗体 4G2 和 2H2 的情况下，我们使用人类髓样细胞系中 DENV-1 感染的 ADE 模型，发现 C1q 使 K562 细胞中 DENV-1 的 ADE 降低了近 40 倍，但对 U937 细胞没有影响。在 K562 细胞中，C1q 减少了 DENV-1/4G2 的吸附，并对 DENV-1/2H2 的吸附和内化产生双重抑制作用。抗体存在时不同的内吞途径对应于 C1q 产生差异作用的条件。此外，C1q 不影响 FcγR 介导的人类髓样细胞中的固有细胞反应。C1q 对 DENV-1 的 ADE 调节取决于免疫细胞上表达的 FcγR 和组成免疫复合物的抗体的特异性。了解针对 DENV 感染的体液免疫反应中的保护性和致病性机制对于成功设计抗病毒药物和疫苗至关重要。
