Mast Cells in Dengue Pathology and Prevention

描述（由申请人提供）：登革热病毒（DENV）是引起急性发热和衰弱疾病登革热和登革出血热（DHF）的原因。这些疾病每年影响约5000万人，使获得许可的登革热疫苗成为全球卫生重点。DENV是一种单链RNA病毒，有四种血清型感染世界各地的人群，但目前没有有效的DENV疫苗。虽然每种血清型的初次感染通常导致疾病迅速得到控制，但不同血清型的第二次感染可能导致致命的并发症，部分原因是存在有害的交叉反应性抗体。这些问题突出了优化任何疫苗配方的必要性，以促进对所有血清型的保护性适应性免疫反应，避免有害的副作用。肥大细胞（MC）存在于宿主-环境界面的组织中，如皮肤，感染登革热病毒的蚊子在皮肤上沉积病毒，并分布在整个结缔组织中。虽然在细菌感染期间，MCs在促进最佳免疫方面的作用已经被很好地描述，但MCs也被认为对某些炎症状况有有害的贡献。很少有研究专门研究MCs与病毒感染和DENV感染的相互作用。我们之前的工作和初步数据表明，MCs对DENV有强烈反应，当DENV感染局限于皮肤时，可以限制DENV感染的传播。然而，初步数据还表明，当DENV病毒颗粒大量系统性存在时，MCs可导致血管渗漏，特别是当MCs在继发性感染期间被异源抗DENV抗体致敏时。在这里，我们建议扩展这些观察结果，以研究MCs在动员针对DENV的保护性免疫以应对原发性或同源继发性攻击中的作用，并检查它们对不同血清型继发性攻击并发症的贡献（如果有的话）。此外，通过利用MCs提供DENV早期保护的能力，我们可以防止建立全身性感染。当加入疫苗时，MC激活剂可以通过引起强大的免疫反应而作为强效佐剂。因此，最后，我们建议开发一种新的疫苗策略，选择性地利用MCs扩增和增强保护性适应性免疫反应的能力，同时产生针对所有DENV血清型的高亲和力抗体和生产性细胞免疫。

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.