Amazonian Center of Excellence in Malaria Research

项目总结 先天免疫和获得性免疫在全身性炎症及发病机制中均起重要作用。 疟疾以及宿主对疟原虫感染的抵抗力。当病人出现疾病症状时，他们会 一般寻求根治疗法，从而阻断潜在的传播。相比之下，拥有 至少在理论上，无症状疾病仍然是疾病的蓄水池。在这个项目中，我们将解决 与先天和后天免疫反应有关的问题，这些问题与理解 无症状疟疾患者的出现和持续。我们之前在美国的流行病学研究 亚马逊认为，多重疟疾感染会导致大量免疫力，这种免疫力是能够控制的，但不是 消除疟疾感染。与急病患者相比，疟疾免疫个体没有表现出 全身炎症和疾病征兆。我们的总体假设是先天免疫细胞来自 低而持久的寄生虫血症患者对疟原虫刺激反应迟钝 预防全身炎症，但同时无法促进获得性免疫 有效消除感染的反应。我们认为，尽管寄生虫血症水平较低，但 预计每次蚊子叮咬的传播率较低，这样的患者长期仍会感染 这是一段时间，因此是亚马逊消除疟疾努力的无声障碍。在这 项目中，我们建议比较疟原虫感染引起的先天性免疫反应和获得性免疫反应。 急性疾病和无症状的患者，并确定潜在参与调节 无症状疟疾患者的全身炎症和防止寄生虫清除。我们的首要目标是 临床和非临床疾病患者天然免疫细胞炎症反应和反应性的比较 无症状的疟疾患者。在第二个目标中，我们将比较体液和细胞的发展 获得性免疫反应以及可能影响高、低水平的免疫调节机制 急性与无症状间日疟原虫或恶性疟原虫患者的先天免疫反应 感染。最后，在目标3中，我们将在纵向研究中调查各种免疫学、寄生虫学和 反复感染患者的临床指标。我们打算验证AIMS 1中定义的生物标记物 和2，并询问无症状的患者是否容易在复发时发展为无疾病 感染。我们还将寻找有症状和无症状的肺炎支原体传染性的免疫学相关性。 殖民时期的间日疟原虫。亲爱的蚊子。这些实验的结果将确定先天的 免疫生物标记物以及B和T细胞反应可预测疾病结局和蚊子 变速箱。如果成功，我们的研究将为监测无症状感染提供重要信息。 感染的无症状个体和潜在的新见解，以进一步控制疟疾在低收入人群中的传播 地方病流行地区。

PROJECT SUMMARY Both the innate and acquired immunity play important roles on systemic inflammation and pathogenesis of malaria as well as host resistance to Plasmodium infection. When patients are symptomatic with disease, they generally seek curative therapy, thus interrupting potential transmission. In contrast, individuals with asymptomatic disease, at least in theory, remain as reservoirs of disease. In this project, we will address questions related to the innate and acquired immune responses that are relevant to understanding the emergence and persistence of asymptomatic malaria individuals. Our previous epidemiological studies in the Amazon suggest that multiple malaria infections result in substantial immunity, which is able to control, but not eliminate malaria infection. In contrast to the acutely ill patients, the malaria immune individuals do not display systemic inflammation and signs of disease. Our overall hypothesis is that innate immune cells from individuals with low and persistent parasitemia, become hyporesponsive to Plasmodium stimulation preventing systemic inflammation, but at the same time being unable to promote an acquired immune response that is efficient in eliminating infection. We believe that despite the low levels of parasitemia, and the predicted low rate of transmission per mosquito bite, such patients continue to be infective over long periods of time and hence represent a silent barrier to efforts to eliminate malaria in the Amazon. In this project, we propose to compare the innate and acquire immune responses elicited by Plasmodium infection in acutely ill and asymptomatic patients, and to define mechanisms that are potentially involved in modulating the systemic inflammation and preventing parasite elimination in asymptomatic malaria patients. Our first aim is to compare the inflammatory response and responsiveness of innate immune cells from clinically ill and asymptomatic malaria patients. In the second aim we will compare the development of humoral and cellular acquired immune responses as well as immunoregulatory mechanisms that may influence hyper and hypo innate immune responses in patients undergoing acute versus asymptomatic P. vivax or P. falciparum infection. Finally, in Aim 3 we will investigate in longitudinal studies, various immunological, parasitological and clinical parameters in patients with recurrent infection. We intend to validate the biomarkers defined in Aims 1 and 2, and to interrogate whether asymptomatic patients are prone to develop no diseases in recurrent infections. We will also search for immunological correlates of infectivity of symptomatic and asymptomatic P. vivax parasitemics for colonized An. darlingi mosquitoes. Outcomes of these experiments will identify innate immune biomarkers as well as B and T cell responses that are predictive of disease outcome and mosquito transmission. If successful, our studies will provide important information for monitoring silent infection in infective asymptomatic individuals and potentially new insights to further control malaria transmission in hypo- endemic areas.