UHI COBRE: P2: IMMUNOPATHOGENESIS OF DENGUE VIRUS INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 登革热、登革出血热(DHF)和登革休克综合征(DSS)从致死率和致死率高的角度来看，已成为世界范围内最重要的节肢动物传播的人类病毒性疾病。这些疾病是由免疫介导的，这一点是毋庸置疑的，但对单一登革热病毒血清型初次感染后T细胞反应的了解不足，阻碍了对疾病严重程度的宿主决定因素的更好理解。这项研究项目的目的是确定人类在最初感染登革热病毒几个月到几十年后的CD4+和CD8+T淋巴细胞反应。核心假设是，登革病毒血清型特异性记忆T细胞在异种登革病毒抗原刺激下，释放细胞因子，参与DHF/DSS的免疫发病机制。拟议的为期五年的研究将通过追求以下具体目标来检验我们的假设： 1.确定初次感染后登革病毒1型血清特异性T细胞反应的特异性和持续时间，并评估异种登革病毒抗原刺激后T细胞的反应性。 2.用流式细胞仪检测登革病毒特异性T细胞的促炎细胞因子反应。 3.描述登革热病毒感染后病毒血症、免疫激活标志物和T细胞反应之间的关系。将研究2001-2002年夏威夷登革热暴发期间和1945年上一次登革热暴发期间感染的个体的血清特异性T细胞反应和对异种登革热病毒抗原的T细胞反应性。 这个项目是创新的，因为它将提供关于单一登革热病毒血清型初次感染的细胞介导免疫反应的特异性和持续时间的新知识。从该项目获得的新知识将对指导登革热和DHF/DSS疫苗的开发产生重大影响，特别是在热带亚太地区。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. From the standpoint of causing high morbidity and mortality, dengue fever, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) have emerged as the most important arthropod-borne viral diseases of humans worldwide. That these diseases are immune-mediated is undisputed, but insufficient knowledge about the T-cell responses following primary infection with a single dengue virus serotype has hampered a better understanding of the host determinants of disease severity. The objective of this research project is to determine the CD4+ and CD8+ T-lymphocyte responses in humans months to decades following primary dengue virus infection. The central hypothesis is that dengue virus serotypespecific memory T cells, upon stimulation with heterologous dengue virus antigens, release cytokines which contribute to the immunopathogenesis of DHF/DSS. The proposed five-year study will test our hypothesis by pursuing the following specific aims: 1. Determine the specificity and duration of dengue virus serotype 1-specific T-cell responses following primary infection, and assess T-cell reactivity following stimulation with heterologous dengue virus antigens. 2. Characterize the proinflammatory cytokine responses of dengue virus-specific T cells by flow cytometry. 3. Characterize the relationship between viremia, immune-activation markers, and T-cell responses following primary dengue virus infection. Serotype-specific T-cell responses and T-cell reactivity to heterologous dengue virus antigens will be studied in individuals infected during the dengue fever outbreak in Hawaii in 2001-2002, and those infected during the previous outbreak in 1945. This project is innovative because it will provide new knowledge about the specificity and duration of cell-mediated immune responses to primary infection with a single dengue virus serotype. Newfound knowledge from this project will have a significant impact on guiding vaccine development for dengue fever and DHF/DSS, particularly in the tropical Asia-Pacific region.