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，控制亚临床个体的利什曼病 巴西乳杆菌感染是通过先天免疫反应以及皮肤相关细胞因子和 CD8+ T 细胞参与导致皮肤利什曼病 (CL)、粘膜利什曼病发展的组织损伤 利什曼病和传播性利什曼病（DL）。主要目标是：艾米）确定先天性如何 细胞控制巴西乳杆菌寄生虫。我们的发现是，大量个体（亚临床） 被巴西乳杆菌感染将控制寄生虫而不发展疾病提供了独特的机会 定义巴西乳杆菌如何产生自然抗性。我们建议： a) 定义 嗜中性粒细胞和巨噬细胞杀死寄生虫的机制； b) 确定中性粒细胞是否 患有不同形式疾病的患者的巨噬细胞表现出不同的杀伤能力 寄生虫；目标2) 确定哪些皮肤相关细胞因子对病理反应有贡献 巴西乳杆菌感染后。我们发现胸腺基质淋巴细胞生成素（TSLP）是一种产生的细胞因子 由屏障表面的上皮细胞产生，在 CL 患者病变的表皮中高度表达。我们 建议：a) 确定 TSLP 对感染李斯特菌的巨噬细胞和树突状细胞 (DC) 的影响。 巴西人; b)确定TSLP在CD4+T和CD8+T细胞增殖和功能中的作用；和c) 将不同临床表型病变中 TSLP 的表达与 T 细胞功能相关联。目标3) 至 确定 CD8 T 细胞如何参与巴西乳杆菌感染患者的免疫病理学。自从 我们的初步数据表明，随着病变恶化，CD8 T 细胞表现出颗粒酶水平增加，我们 假设 CD8 T 细胞导致患者出现病理，并建议：a) 确定 CD8+ T 细胞募集到皮肤病变部位的机制； b) 确定 血液中炎症与调节性 CD8+ T 细胞亚群的频率和平衡 CL 患者的病变； c) 比较来自 SC 个体和 CL 患者的 CD8+ T 细胞的能力 促进体外杀死巴西乳杆菌感染的巨噬细胞。