The Role of Dengue Virus Antibodies in Vector-independent transmission of Zika Virus

登革热病毒抗体在寨卡病毒媒介独立传播中的作用

基本信息

批准号：
10470145
负责人：
Cesar Augusto Lopez
金额：
$ 4.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470145
关键词：
Active Biological Transport Address Americas Antibodies Antibody Response Antibody-mediated protection Area Benign Binding Biological Assay Blindness Capsid Caribbean region Cells Clinic Congenital Abnormality Cross Infection Culicidae Cytomegalovirus Cytoplasm Defect Dengue Infection Dengue Vaccine Dengue Virus Development Disease Doctor of Philosophy Endosomes Epidemiology Epithelial Cells Epitopes Fc Receptor Female Female genitalia Fetus Fever Flavivirus Genome Goals Human Humoral Immunities Image Immobilization Immune Immunity Immunoglobulin G Immunoglobulins Immunologics Infection Infectious Diseases Research Invaded Latin America Lead Location Mediating Membrane Fusion Microcephaly Microscopy Modeling Mucins Mucous body substance Mus National Institute of Allergy and Infectious Disease North Carolina Passive Immunity Pathway interactions Patients Peru Physicians Placenta Pregnancy Process Public Health Research Support Resistance Risk Role Route Rural Sampling Schools Scientist Seizures Serology Serology test Sexual Transmission Simplexvirus Syncytiotrophoblast Testing Training Travel Vagina Viral Virion Virus Virus Diseases Woman ZIKV infection Zika Virus Zika virus vaccine career congenital infection congenital zika syndrome cross reactivity experience experimental study fetal genital secretion hearing impairment monolayer mosquito-borne mouse model neonatal Fc receptor neonate neutralizing antibody particle pathogen prevent receptor binding reproductive tract transcytosis transmission process vaccine development vector vector mosquito viral transmission

项目摘要

Project Summary/Abstract Zika virus (ZIKV) emerged in the Americas in 2015 and has since been recognized to cause neurodevelopmental defects including vision and hearing loss, seizures, microcephaly, and fetal demise (congenital Zika syndrome). ZIKV is now endemic throughout Latin America and the Caribbean, where the related flavivirus dengue virus (DENV), is highly prevalent, transmitted by the same mosquito vector. DENV and ZIKV share significant antigenic cross-reactivity but these cross-reactive antibodies are not cross-neutralizing, creating the potential for DENV antibodies to impact ZIKV transmission and disease. ZIKV also can be transmitted through sexual contact and either transmission route may result in congenital disease. Neutralizing IgG antibodies are important for protection from mosquito-borne transmission and in preliminary studies, humoral immunity appears to be the most important adaptive immune component in restricting vaginal ZIKV infection. IgG-coated viral particles can be trapped in vaginal mucus by IgG-mucin interactions, allowing non-neutralizing IgG to contribute to protection against sexually transmission. In Aim 1 I will test my hypothesis that both neutralizing and non-neutralizing IgG contribute to protection from ZIKV intravaginal infection. I will image IgG-bound ZIKV in vaginal mucus, study ZIKV binding epitopes of IgG in human genital secretions, and determine if both neutralizing and non-neutralizing monoclonal IgG can protect against ZIKV intravaginal inoculation in a mouse model. IgG is actively transported across the placenta via the neonatal Fc receptor (FcRn), expressed in syncytiotrophoblasts. FcRn binds to IgG at a slightly acidic pH and redirects endosomal IgG away from lysosomal degradation. This mechanism contributes to transplacental transmission of human cytomegalovirus (HCMV). ZIKV cell entry is pH sensitive, so transcytosis by this mechanism requires IgG-bound ZIKV to remain infectious during endosomal acidification long enough to be rescued by FcRn. In Aim 2 I will test my hypothesis that in DENV immune women, ZIKV bound to cross-reactive but non-neutralizing antibodies can “hitchhike” across the placenta via FcRn mediated transcytosis. I will use a Transwell culture model to study FcRn- dependent transcytosis, and fusion assays and microscopy to determine pH of fusion for ZIKV. I aim to characterize the role of DENV antibodies in vector-independent transmission of ZIKV, a paradigm change for flavivirus serology, a project within the goals of the NIAID. Enclosed is also a training plan for myself to obtain an MD/PhD, with research support through Dr. Helen Lazear and Dr. Aravinda de Silva, who together have extensive experience studying flavivirus immunity. During graduate school, I will be seeing patients with Dr. Sylvia Becker-Dreps at a rural clinic in North Carolina, a large proportion of which only speak Spanish. Additionally, I will be traveling to Peru under Dr. Natalie Bowman to collect samples for this proposal. This proposal will train me for a career in global infectious disease research as a physician scientist.

项目摘要/摘要 Zika病毒（ZIKV）于2015年在美洲出现，此后被认为会导致神经发育缺陷，包括视力和听力丧失，癫痫发作，小头畸形和胎儿灭亡（先天寨卡综合症）。 Zikv现在是整个拉丁美洲和加勒比海的内在人物，那里相关的黄病毒登革热病毒（DENV）高度普遍，由同一蚊子传播。 denv和 ZIKV具有明显的抗原交叉反应性，但这些交叉反应性抗体并非交叉中和创造了DENV抗体影响ZIKV传播和疾病的潜力。 ZIKV也可以通过性接触传播，任何传输路线都可能导致先天性疾病。中和IgG抗体对于防止蚊子传播很重要在初步研究中，体液免疫学似乎是最重要的适应性免疫学成分限制阴道ZIKV感染。 IgG涂层的病毒颗粒可以被IgG-粘液捕获在阴道粘液中相互作用，允许非中和IgG有助于防止性传播。在目标1 i 将检验我的假设，即中和和非中和IgG都有助于保护ZIKV 阴道内感染。我将在阴道粘液中图像IgG结合的ZIKV，研究IgG的ZIKV结合表位人类生殖器分泌物，并确定中和和非中和单克隆IgG是否可以保护针对小鼠模型中的ZIKV静脉内接种。 IgG通过新生儿FC受体（FCRN）主动运输在整个子宫内合成成素细胞。 FCRN在略微酸性的pH下与IgG结合，并重定向内体IgG远离溶酶体降解。这种机制有助于人类巨细胞病毒的移植传播（HCMV）。 ZIKV细胞进入pH值敏感，因此通过这种机制的转介症需要IgG结合的ZIKV保留内体酸化过程中具有传染性的时间足够长，可以被FCRN营救。在AIM 2中，我将检验我的假设在DENV免疫妇女中，ZIKV必然会交叉反应但非中和抗体可以“搭便车” 通过FCRN介导的转介症穿越整个斑点。我将使用Transwell文化模型研究FCRN- 依赖性转胞病以及融合测定和显微镜，以确定ZIKV融合的pH值。我的目的是表征DENV抗体在Zikv的矢量独立传播中的作用，A Flavivirus血清学的范式变化，这是NIAID目标范围内的项目。封闭也是一个培训计划让我自己获得MD/PhD，并通过Helen Lazear博士和Aravinda de Silva博士的研究支持，他们共同研究黄病毒免疫的经验。在研究生院期间，我会看到 Sylvia Becker-Dreps博士在北卡罗来纳州的一家粗糙诊所的患者，其中很大一部分仅说话西班牙语。此外，我将在娜塔莉·鲍曼（Natalie Bowman）博士的带领下前往秘鲁，为此提案收集样本。该建议将训练我作为物理科学家从事全球传染病研究的职业。