Protective and Pathological Immune Responses in L. Braziliensis Infection

巴西乳杆菌感染的保护性和病理性免疫反应

• 批准号: 8501131
• 负责人: Edgar M Carvalho
• 金额: $ 10.29万
• 依托单位: FEDERAL UNIVERSITY OF BAHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501131
• 关键词: Area; Blood; Brazil; CD8B1 gene; Cell physiology; Cells; Clinical; Cutaneous; Cutaneous Leishmaniasis; Data; Dendritic Cells; Development; Disease; Disease Progression; Epidermis; Epithelial Cells; Equilibrium; Exhibits; Frequencies; Granzyme; Health; Human; Immune response; Immunobiology; Immunologic Factors; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Interferons; Knowledge; Leishmania; Leishmania braziliensis; Leishmaniasis; Lesion; Link; Mediating; Natural Immunity; Natural Resistance; Parasite Control; Parasites; Pathologic; Pathology; Patients; Population; Relative (related person); Research Infrastructure; Resistance; Role; Severity of illness; Site; Skin; Staging; Surface; T-Cell Proliferation; T-Lymphocyte; Testing; Thinking; Tissues; clinical phenotype; cohort; comparative; cytokine; cytotoxic; human TSLP protein; immunopathology; killings; macrophage; neutrophil; novel; novel strategies; response; vaccine development

The major hypothesis of this project is that the control of leishmaniasis in individuals with sub-clinical L.braziliensis infection is performed by innate immune response and that skin associated cytokines and CD8+ T cells participate of tissue damage leading development of cutaneous leishmaniasis (CL), mucosal leishmaniasis and disseminated leishmaniasis (DL). The major aims are: Aimi) To determine how innate cells control L. braziliensis parasites. Our finding that a large number of individuals (subclinical) who are infected by L.braziliensis will control the parasites without developing disease provides a unique opportunity to define how natural resistance may be occurring to L.braziliensis. We propose to: a) define the mechanism(s) involved in the killing of parasites by neutrophils and macrophages; b) determine if neutrophils and macrophages from patients with different forms ofthe disease exhibit differences in their capacity to kill parasites; Aim2) To determine what skin-associated cytokines contribute to the pathologic responses following L. braziliensis infecfion. We found that thymic stromal lymphopoietin (TSLP), a cytokine produced by epithelial cells at barrier surfaces, is highly expressed in the epidermis of lesions from CL pafients. We propose to: a) determine the effect of TSLP in macrophage and dendritic cells (DCs) infected with L. braziliensis; b) determine the role of TSLP in CD4+ T and CD8+ T cell proliferation and funcfion; and c) correlate the expression of TSLP in lesions from different clinical phenotypes with T cell function. Aim3) To determine how CD8 T cells participate in the immunopathology in patients infected with L. braziliensis. Since our preliminary data indicate that CD8 T cells exhibit increased levels of granzyme as the lesions worsen, we hypothesize that CD8 T cells contribute to the pathology seen in patients, and propose to: a) determine the mechanisms involved in the recruitment of CD8+ T cells to cutaneous lesion sites; b) determine the frequency and the balance of inflammatory versus regulatory CD8+ T cell subpopulations in the blood and lesions from CL patients; and c) compare the ability of CD8+ T cells from SC individuals and CL patients to promote killing of L. braziliensis infected macrophages in vitro.

该项目的主要假设是，亚临床利什曼病患者的控制 巴西乳杆菌感染是通过先天免疫应答进行的，皮肤相关的细胞因子和 CD 8 + T细胞参与导致皮肤利什曼病（CL）、粘膜利什曼病（CL）、 利什曼病和播散性利什曼病（DL）。主要目的是：艾米）为了确定如何先天 细胞对照L.巴西寄生虫我们发现，大量的人（亚临床）谁是 感染巴西乳杆菌的人将控制寄生虫而不发展疾病提供了一个独特的机会 来确定巴西乳杆菌的天然耐药性是如何产生的。我们建议：a）界定 参与嗜中性粒细胞和巨噬细胞杀死寄生虫的机制; B）确定嗜中性粒细胞是否 而来自不同疾病患者的巨噬细胞在杀伤能力上表现出差异 目的2）确定哪些皮肤相关细胞因子参与病理反应 关注L.巴西侵染我们发现，胸腺基质淋巴细胞生成素（TSLP），一种细胞因子， 由屏障表面的上皮细胞表达，在CL患者病变的表皮中高度表达。我们 本研究拟：a）测定TSLP对感染L. B）确定TSLP在CD 4 + T和CD 8 + T细胞增殖和功能中的作用;和c） TSLP在不同临床表型的病变中的表达与T细胞功能相关。目标3） 确定CD 8 T细胞如何参与感染L.巴西。以来 我们的初步数据表明，随着病变的恶化，CD 8 T细胞表现出颗粒酶水平的增加， 假设CD 8 T细胞对患者中所见的病理有贡献，并提出：a）确定 涉及将CD 8 + T细胞募集到皮肤损伤部位的机制; B）确定 血液中炎性与调节性CD 8 + T细胞亚群的频率和平衡， c）比较来自SC个体和CL患者的CD 8 + T细胞与来自SC个体和CL患者的CD 8 + T细胞的能力， 促进L. braziliensis感染的巨噬细胞。