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 先天和获得的免疫都在系统性炎症和发病机理上起重要作用 疟疾以及宿主对疟原虫感染的抗性。当患者对疾病有症状时，他们 通常寻求治疗疗法，从而中断潜在的传播。相比之下，个人 至少从理论上讲，无症状疾病仍然是疾病的储层。在这个项目中，我们将解决 与与先天和获得的免疫反应有关的问题，与理解有关 无症状疟疾个体的出现和持久性。我们以前在 亚马逊建议多种疟疾感染会导致实质性免疫力，这能够控制，但不能 消除疟疾感染。与急性疾病的患者相反，疟疾免疫个体不显示 系统性炎症和疾病迹象。我们的总体假设是，先天免疫细胞来自 患有低和持续寄生虫血症的个体，对疟原虫刺激的反应不足 防止系统性炎症，但同时无法促进获得的免疫 有效消除感染的反应。我们认为，尽管寄生虫血症水平较低，并且 预测的每蚊子叮咬的传播率低，此类患者长期继续感染 一段时间，因此代表了消除亚马逊疟疾的努力的沉默障碍。在这个 项目，我们建议比较先天性并获得疟原虫感染引起的免疫反应 急性病和无症状患者，并定义可能参与调节的机制 无症状疟疾患者的全身性炎症和防止寄生虫消除。我们的第一个目标是 比较先天免疫细胞从临床上疾病和 无症状疟疾患者。在第二个目标中，我们将比较体液和蜂窝的发展 获得的免疫反应以及可能影响超级和低调的免疫调节机制 患有急性和无症状疟原虫或恶性疟原虫的患者的先天免疫反应 感染。最后，在AIM 3中，我们将在纵向研究中调查各种免疫学，寄生学和 复发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，并询问无症状的患者是否容易发生疾病 感染。我们还将寻找有症状和无症状的感染性的免疫学相关性。 殖民的寄生虫学。亲爱的蚊子。这些实验的结果将确定先天 免疫生物标志物以及B和T细胞反应，可预测疾病结果和蚊子 传播。如果成功，我们的研究将提供重要的信息，以监测 感染无症状的个体和潜在的新见解，以进一步控制疟疾的传播 流行地区。