Understanding the mechanisms of antibody-mediated transcytosis of ZIKV within the placenta

了解胎盘内抗体介导的 ZIKV 转胞吞作用机制

• 批准号: 10624960
• 负责人: Mehul Shamal Suthar
• 金额: $ 75.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-11 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624960
• 关键词: Address; Adult; Affinity; Americas; Antibodies; Antibody Response; Antibody Specificity; Antigen-Antibody Complex; Bathing; Binding; Biological Assay; Biological Models; Biology; Blood; Brazil; Cells; Chorionic villi; Congenital Abnormality; Dengue; Dengue Virus; Environment; Epidemic; Fab Immunoglobulins; Fc Receptor; Fc domain; Flavivirus; Flavivirus Infections; Gases; Generations; Gestational Age; Goals; Guillain Barré Syndrome; Histologic; Homeostasis; Human; Humoral Immunities; IgG Receptors; IgG1; IgG2; IgG3; IgG4; Immune response; Immunoglobulin G; Immunologics; Infection; Inflammation; Inflammatory Response; Integration Host Factors; Link; Macrophage; Mediating; Microcephaly; Modeling; Monoclonal Antibodies; Mothers; Neonatal; Nutrient; Observational epidemiology; Outcome; Pathogenesis; Pathway interactions; Penetration; Placenta; Placentation; Play; Pregnancy; Pregnant Women; Primary Infection; Public Health; RNA; Reporting; Serum; Specificity; Spontaneous abortion; Symptoms; Syncytiotrophoblast; System; Transportation; Uterus; Vascular blood supply; Villous; Villus; Viral; Virion; Virus; ZIKA; ZIKV infection; Zika Virus; cross reactivity; fetal; fetal blood; insight; mRNA sequencing; mosquito-borne; neonatal Fc receptor; neutralizing antibody; permissiveness; placental infection; receptor expression; secondary infection; therapeutic target; transcytosis; vaccine development; wasting

Humoral immunity is an essential component of the immune response to flavivirus infection. Primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome are hotly debated and controversial. Zika virus (ZIKV) is a mosquito-borne flavivirus, which has a high degree of sequence and structural homology to Dengue virus (DENV), and is responsible for continuing epidemics of fetal congenital malformations within the Americas since its introduction to Brazil in 2015. Prior flavivirus exposure has been strongly associated with generation of cross-reactive antibodies that bind to and/or neutralize ZIKV. A unique aspect of ZIKV pathogenesis is the ability of the virus to seed infection within the placenta, however, the mechanisms of transplacental ZIKV infection are not well understood. The overall goal of this proposal is to understand how cross-reactive antibodies facilitate ZIKV transcytosis and seed infection of the placenta. The placenta is composed of anchoring chorionic villi, which penetrate the uterine wall, as well as floating chorionic villi that are bathed in maternal blood pooling in the intervillous space. Recent epidemiological observations found that between 20-50% of pregnant women with possible ZIKV exposure had detectable ZIKV RNA in the placenta. Another report found that ZIKV can persist in the placenta for over 200 days post mother onset of Zika symptoms. We discovered that Hofbauer cells, fetally- derived placental macrophages located within the villus stroma, are permissive for ZIKV infection. To identify a potential mechanism by which ZIKV gains access to the villous stroma, we recently evaluated the impact of cross-reactive dengue antibodies in mediating transplacental infection. Using an ex vivo placental explant model, we observed profound enhancement of ZIKV infection of human mid-gestation floating chorionic villi with ZIKV immune complexes generated using either DENV or ZIKV cross-reactive convalescent serum or monoclonal antibodies. Similar to histological analysis of placenta from infected pregnant mothers, ZIKV replicated exclusively within Hofbauer cells. Based on these observations, we hypothesize that the Fab fragment (specificity for ZIKV) and the Fc domain (affinity for FcRn and FcγR) of IgG impacts antibody-mediated ZIKV transplacental infection. Moreover, we believe that gestational age of the placenta dynamically influences the efficiency of ZIKV transcytosis and placental infection. Moreover, we believe that gestational age of the placenta dynamically impacts ZIKV transcytosis and placental infection. In this proposal, we seek to address the following outstanding questions: 1) How does IgG antibody specificity, affinity and Fc/FcRn interactions impact ZIKV transplacental infection? and 2) How does placental gestational age impacts antibody-mediated infection of Hofbauer cells? Our studies will likely reveal therapeutic targets and provide insights for development a vaccine to protect against ZIKV infection.

体液免疫学是对黄病毒感染免疫激发的重要组成部分。原发性感染产生了稳健的中和抗体反应，可介导病毒控制和保护。越来越明显的是，具有密切相关的黄病毒菌株的继发感染会导致免疫交叉反应性。但是，感染结果的后果是激烈的争议和争议。 Zika virus (ZIKV) is a mosquito-borne flavivirus, Which has a high degree of sequence and structural homology to Dengue virus (DENV), and is responsible for continuing episodes of fetal congenital malformations within the Americas since its introduction to Brazil in 2015. Prior flavivirus exposure has been strongly associated with generation of cross-reactive antibodies that bind to and/or neutralize zikv。 ZIKV发病机理的一个独特方面是病毒在多余体内种子感染的能力，但是，尚不清楚移植ZIKV感染的机制。该提案的总体目标是了解交叉反应性抗体如何支持ZIKV转胞膜和种子感染。斑点由锚固的绒毛膜绒毛，这些绒毛膜穿透了子宫壁，以及浮动的绒毛膜绒毛，这些绒毛在Intercillus空间中沐浴在母体血液中。最近的流行病学观察发现，有20％至50％的ZIKV暴露于暴露的孕妇已经检测到PLACETA中的ZIKV RNA。另一份报告发现，在母亲发作后，Zikv可以在Zika症状发作后持续200天以上。我们发现，位于绒毛基质内的遗体衍生的斑点巨噬细胞的Hofbauer细胞是允许ZIKV感染的。为了确定ZIKV获得进入绒毛基质的潜在机制，我们最近评估了交叉反应性风扇在介导移植感染中的影响。使用离体胎盘模型，我们观察到使用DENV或ZIKV交叉反应疗法血清或单克隆抗体产生的ZIKV免疫复合物对人类中期浮动绒毛绒毛的ZIKV感染深刻增强。类似于感染怀孕母亲的胎盘的组织学分析，ZIKV仅在Hofbauer细胞中复制。基于这些观察结果，我们假设IgG的Fab片段（ZIKV的特异性）和FC域（FCRN和FCγR的亲和力）会影响抗体介导的ZIKV ZIKV移植感染。此外，我们认为胎盘的妊娠年龄会动态影响ZIKV跨介症和斑点感染。在此提案中，我们试图解决以下杰出问题：1）IgG抗体特异性，亲和力和FC/FCRN相互作用如何影响ZIKV ZIKV移植感染？ 2）斑点胎龄如何影响抗体介导的Hofbauer细胞感染？我们的研究可能会揭示治疗靶标，并为开发疫苗提供见解，以防止ZIKV感染。