B cell receptor dependent enhancement of dengue virus infection.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
PLoS Pathogens Pub Date : 2024-10-31 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012683
Chad Gebo, Céline S C Hardy, Benjamin D McElvany, Nancy R Graham, Joseph Q Lu, Shima Moradpour, Jeffrey R Currier, Heather Friberg, Gregory D Gromowski, Stephen J Thomas, Gary C Chan, Sean A Diehl, Adam T Waickman
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Abstract

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into FcγR expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectible B cells increases in previously flavivirus-naïve volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.

B 细胞受体依赖性增强登革热病毒感染。
登革热病毒(DENV)是登革热的病原体,登革热是一种由蚊子传播的疾病,对全世界的公共卫生造成了日益严重的负担。登革热的一个独特病理生理学特征是免疫介导的增强,即原发感染引起的原有免疫力会增强异源登革热病毒血清型后续感染的严重程度。对这一现象的主要机理解释是抗体依赖性增强(ADE),即亚中和浓度的 DENV 特异性 IgG 抗体可促进 DENV 进入 FcγR 表达细胞,如单核细胞、巨噬细胞和树突状细胞。因此,该模型认为吞噬性单核细胞是 DENV 的主要贮存库。然而,对急性 DENV 感染者样本的分析表明,B 细胞是最大的受感染循环细胞库,这表明我们对免疫介导的 DENV 趋向性的理解出现了脱节。在这项研究中,我们证明了 DENV 特异性 B 细胞受体(BCR)的表达使细胞极易感染 DENV,膜限制性 BCR 的感染增强活性与抗体 IgG 版本的 ADE 潜力相关。此外,我们还观察到,以前对黄病毒免疫的志愿者在初次感染 DENV 后,其可被 DENV 感染的 B 细胞的频率会增加。这些发现表明,B细胞的BCR依赖性感染是免疫介导的增强DENV感染的一种新机制。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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