UHI COBRE: P2: IMMUNOPATHOGENESIS OF DENGUE VIRUS INFECTION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。从发病率和死亡率高的角度来看，登革热、登革出血热（DHF）和登革休克综合征（DSS）已成为世界范围内最重要的人类节肢动物传播的病毒性疾病。这些疾病是免疫介导的，这是无可争议的，但对原发性感染单一登革热病毒血清型后t细胞反应的认识不足，阻碍了对疾病严重程度的宿主决定因素的更好理解。本研究项目的目的是确定原发性登革热病毒感染后数月至数十年人类CD4+和CD8+ t淋巴细胞反应。中心假设是登革热病毒血清型特异性记忆T细胞在受到外源登革热病毒抗原刺激后释放细胞因子，促进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：确定原发性感染后登革热病毒血清型1特异性t细胞反应的特异性和持续时间，并评估异源登革热病毒抗原刺激后的t细胞反应性。2. 用流式细胞术表征登革病毒特异性T细胞的促炎细胞因子反应。3. 描述原发性登革热病毒感染后病毒血症、免疫激活标记物和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感染的个体和1945年上次暴发期间感染的个体的血清型特异性t细胞反应和t细胞对异源登革热病毒抗原的反应性。该项目具有创新性，因为它将提供关于细胞介导的免疫反应对单一登革热病毒血清型原发性感染的特异性和持续时间的新知识。该项目的新知识将对指导登革热和登革出血热/腹泻病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.