Amazonian Center of Excellence in Malaria Research

亚马逊疟疾研究卓越中心

• 批准号: 10598090
• 负责人: RICARDO TOSTES GAZZINELLI
• 金额: $ 27.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598090
• 关键词: Acute; Anti-DNA Antibodies; Antibodies; Antibody Formation; Antigens; Area; B-Lymphocyte Subsets; B-Lymphocytes; Biological Markers; Bite; Brazil; CD8-Positive T-Lymphocytes; CTLA4 gene; Cell physiology; Cells; Chills; Clinical; Communities; Culicidae; Dendritic Cells; Development; Diagnosis; Disease; Disease Outcome; Disease Reservoirs; Epigenetic Process; Equilibrium; Fever; Growth; Headache; Host resistance; Human; IL17 gene; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Immunology; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type II; Interleukin-2; Interleukin-4; Interleukin-5; Interruption; Lead; Learning; Longitudinal Studies; Malaria; Mediating; Memory; Merozoite Surface Protein 1; Modeling; Monitor; Natural Immunity; Nucleic Acids; Outcome; Parasite Control; Parasitemia; Parasites; Parasitology; Pathogenesis; Patients; Peru; Phagocytes; Plasma; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Play; Population; Process; Production; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Role; Sampling; Side; Signs and Symptoms; Stimulus; Superoxides; Symptoms; T cell response; T-Lymphocyte; TNF gene; Testing; Time; Toll-like receptors; acquired immunity; biomarker identification; biomarker validation; cell mediated immune response; circulating biomarkers; clinical predictors; curative treatments; cytokine; epidemiology study; experimental study; histone modification; immunoregulation; insight; mRNA Expression; malaria infection; malaria transmission; microbial; monocyte; neutrophil; novel vaccines; predicting response; predictive marker; prevent; programmed cell death protein 1; prospective; receptor; recurrent infection; response; systemic inflammatory response; theories; transmission process; vector mosquito

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.

项目摘要 先天性和获得性免疫在全身炎症反应和炎症反应的发生、发展中起着重要作用。 疟疾以及宿主对疟原虫感染的抵抗力。当患者出现疾病症状时， 一般寻求治愈性治疗，从而阻断潜在的传播。相反， 至少在理论上，无症状疾病仍然是疾病的储存库。在这个项目中，我们将解决 与先天性和获得性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。我们以前在美国的流行病学研究 亚马逊建议，多种疟疾感染导致大量的免疫力，这是能够控制，但不是 消除疟疾感染。与急性病患者相比，疟疾免疫个体不显示 全身炎症和疾病迹象。我们的总体假设是，先天免疫细胞从 低水平和持续性寄生虫血症的个体对疟原虫刺激反应迟钝 预防全身性炎症，但同时不能促进获得性免疫 这是一种有效的消除感染的反应。我们相信，尽管寄生虫血症水平较低， 由于预测的每次蚊子叮咬的传播率很低，这些患者在很长一段时间内仍然具有传染性 因此，这是亚马逊地区消除疟疾努力的无声障碍。在这 项目，我们建议比较先天性和获得性免疫反应引起的疟原虫感染， 急性病和无症状的患者，并确定机制，可能涉及调节 全身炎症和预防无症状疟疾患者的寄生虫清除。我们的首要目标是 比较来自临床疾病的先天免疫细胞的炎症反应和反应性， 无症状疟疾患者。在第二个目标中，我们将比较体液和细胞的发展， 获得性免疫应答以及可能影响高和低免疫应答的免疫调节机制。 急性间日疟原虫或恶性疟原虫感染者与无症状间日疟原虫或恶性疟原虫感染者的天然免疫应答 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 复发性感染患者的临床参数。我们打算验证目标1中定义的生物标志物 和2，并询问无症状患者是否易于在复发中发展为无疾病， 感染.我们还将寻找有症状和无症状的疟原虫感染性的免疫学相关性。 间日疟原虫寄生虫的殖民。达林吉蚊子。这些实验的结果将确定先天的 免疫生物标志物以及预测疾病结果和蚊子的B和T细胞应答 传输如果成功，我们的研究将为监测沉默感染提供重要信息。 感染性无症状个体和潜在的新见解，以进一步控制疟疾传播的低， 地方病流行区。