Mast Cells in Dengue Pathology and Prevention

肥大细胞在登革热病理学和预防中的作用

• 批准号: 8435997
• 负责人: Soman N Abraham
• 金额: $ 36.86万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435997
• 关键词: Acute; Adjuvant; Adverse effects; Affect; Affinity; Antibodies; Antibody Affinity; Bacterial Infections; Blood Vessels; Cells; Cellular Immunity; Connective Tissue; Culicidae; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Deposition; Disease; Disease Outcome; Disease Progression; Drug Formulations; Ensure; Environment; Exposure to; Extravasation; Fever; Health Priorities; Human; Immune; Immune response; Immunity; Immunologic Memory; Individual; Infection; Inflammatory; Lead; Licensing; Memory; Outcome; Pathology; Persons; Play; Polyvalent Vaccine; Population; Prevention; Property; RNA Viruses; Research; Role; Sentinel; Serotyping; Skin; Staging; Systemic infection; Therapeutic; Tissues; Vaccines; Vascular Permeabilities; Virion; Virus; Virus Diseases; Work; global health; mast cell; memory recall; novel strategies; novel vaccines; pathogen; prevent; public health relevance; response; secondary infection; vaccination strategy

DESCRIPTION (provided by applicant): Dengue virus (DENV) is the cause of the acute febrile and debilitating diseases dengue fever and dengue hemorrhagic fever (DHF). These diseases affect an estimated 50 million individuals each year, making a licensed dengue vaccine a global health priority. Four serotypes of DENV, a single stranded RNA virus, infect human populations worldwide but there is currently no effective DENV vaccine. While primary infections of each serotype typically result in a quickly contained illness, a second challenge with a different serotype can lead to lethal complications, in part, due to the presence of harmful cross-reactive antibodies. These issues highlight the imperative of optimizing any vaccine formulation to promote a protective adaptive immune response to all serotypes, avoiding harmful side effects. Mast cells (MC) are present in tissues at the host- environment interface, such as the skin, where DENV-infected mosquitoes deposit virus, and are distributed systemically throughout connective tissues. Although the role of MCs in promoting optimal immunity during bacterial infection is well characterized, MCs are also known for detrimental contributions to certain inflammatory conditions. Few studies have examined interactions of MCs with viral infections and DENV infection, specifically. Our previous work and preliminary data reveal that MCs strongly react to DENV and can limit the spread of DENV infection when localized in the skin. However, preliminary data also suggest that when DENV virus particles are present in large numbers, systemically, MCs can contribute to vascular leakage, particularly when MCs are sensitized with heterologous anti-DENV antibodies during secondary infection. Here, we propose to extend these observations to investigate the role of MCs in mobilizing protective immunity against DENV to primary or homologous secondary challenges and to examine their contribution, if any, to complications of secondary challenge with a different serotype. Furthermore, by capitalizing on the capacity of MCs to offer early protection from DENV, we may prevent the establishment of systemic infection. MC activators, when incorporated in vaccines, can serve as potent adjuvants by evoking a powerful immune response. Therefore, finally, we propose to develop a novel vaccine strategy that selectively harnesses the MCs capacity to amplify and augment protective adaptive immune responses to generate high affinity antibodies and productive cellular immunity simultaneously against all DENV serotypes.

描述（由申请人提供）：登革热病毒（DENV）是急性发热和使人衰弱的疾病登革热和登革热出血热（DHF）的原因。这些疾病每年会影响估计的5000万人，这使得获得许可的登革热疫苗是全球健康的重点。 DENV的四种血清型是一种滞留的RNA病毒，全世界感染了人类种群，但目前尚无有效的DENV疫苗。尽管每种血清型的原发性感染通常会导致疾病快速疾病，但具有不同血清型的第二个挑战可能导致致命并发症，部分原因是存在有害的交叉反应性抗体。这些问题强调了优化任何疫苗配方以促进对所有血清型的保护性适应性免疫反应的必要性，避免了有害的副作用。肥大细胞（MC）存在于宿主环境界面的组织中，例如皮肤，其中DENV感染的蚊子沉积病毒，并系统地分布在整个结缔组织中。尽管MC在促进细菌感染过程中促进最佳免疫力中的作用是充分表征的，但MC也因对某些炎症条件的有害贡献而闻名。很少有研究特别研究了MC与病毒感染和DENV感染的相互作用。我们以前的工作和初步数据表明，MC对DENV有强烈的反应，并且可以限制在皮肤中局部的DENV感染的扩散。但是，初步数据还表明，当大量存在DENV病毒颗粒时，从系统上，MC可以导致血管泄漏，尤其是当MC在继发性感染过程中用异源抗DENV抗体敏感时。在这里，我们建议扩展这些观察结果，以研究MC在动员DENV对主要或同源次要挑战的保护性免疫中的作用，并研究其对次要挑战并以不同血清型的并发症的贡献（如果有的话）。此外，通过利用MC提供DENV早期保护的能力，我们可能会阻止建立系统性感染。 MC激活剂在疫苗中掺入时，可以通过唤起强大的免疫反应来充当有效的佐剂。因此，最后，我们建议制定一种新型的疫苗策略，该疫苗策略有选择地利用MCS的能力来扩增和增强保护性适应性免疫反应，以同时对所有DENV血清型产生高亲和力和生产性细胞免疫。