The role for Notch signaling in inflammatory responses in infectious disease

Notch 信号在传染病炎症反应中的作用

• 批准号: 7935983
• 负责人: Lucas P Carvalho
• 金额: $ 5万
• 依托单位: FEDERAL UNIVERSITY OF BAHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935983
• 关键词: Address; Antigen-Presenting Cells; Antigens; Area; Blood Cells; Brazil; CD14 gene; CD4 Positive T Lymphocytes; Cell Nucleus; Cells; Chronic; Cleaved cell; Clinical; Communicable Diseases; Cutaneous; Cutaneous Leishmaniasis; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; FCGR3B gene; Face; Gene Targeting; Generations; Genetic Transcription; Human; Hypersensitivity skin testing; Immune response; In Vitro; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-10; Interleukin-12; Interleukin-15; Lead; Leishmania; Leishmania braziliensis; Leishmaniasis; Lesion; Ligand Binding; Ligands; Lymphocyte; Maintenance; Mammals; Mediating; Monoclonal Antibodies; Mononuclear; Mus; Nose; Notch Signaling Pathway; Parasite Control; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phagocytes; Population; Production; Recombinants; Recording of previous events; Recruitment Activity; Regulation; Reporting; Role; Signal Transduction; Site; Symptoms; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissues; Toll-like receptors; Tumor Necrosis Factor-alpha; Ulcer; cell type; cytokine; gamma secretase; human TNF protein; immunopathology; inhibitor/antagonist; macrophage; monocyte; notch protein; pathogen; public health relevance; response; transmission process

DESCRIPTION (provided by applicant): Leishmania braziliensis infection can lead to the inflammatory clinical forms of disease, cutaneous (CL) and mucosal leishmaniasis (ML). Peripheral blood mononuclear cells (PBMC) from these individuals secrete high levels of IFN-gamma and TNF-alpha and low levels of IL-10 in response to soluble Leishmania antigen. Lesions of these patients are composed by mononuclear cells infiltrate and very few parasites are observed. Despite the control of parasite multiplication, the immunopathology persists and attempt to modulate inflammatory in-vitro using recombinant IL-10 or monoclonal antibodies anti- IL-12 and anti-IL-15 failed to down-regulate IFN-gamma production in PBMC from these patients, suggesting that another mechanism of regulation of immune response might contribute to pathogenesis of CL and ML. A role of Notch signaling in lymphocyte differentiation, proliferation and cytokine production has been reported. Expression of the Notch ligand, Delta4 in dendritic cells (DCs) was shown to orchestrate differentiation of Th1 cells and, recently, it has been shown that toll like receptor ligand-induced DC and monocytes activation is also dependent upon Notch signaling. Our preliminary data shows that disruption of Notch signaling using gamma secretase inhibitor can decrease Leishmania antigen- induced IFN-gamma production in patients with CL. Also, our data shows that differentiation of human monocytes into CD16+ (pro-inflammatory monocytes) is dependent on gamma secretase activity. In the present proposal we seek to identify the molecules that participate in the Notch signaling (Delta and Jagged) that are involved in the generation and maintenance of inflammatory responses in CL and ML individuals. The patients and controls will be recruited from the L. braziliensis transmission endemic area of Corte de Pedra, Northeastern Brazil. In this endemic area an average of 1000 CL cases and 40 ML cases occurs per year, and our group has been performing clinical and immunological studies in this site for almost three decades. In the endemic are of Corte de Pedra we also found that 15% of the population has positive skin test for Leishmania antigen without symptoms or history of disease. These individuals are known to have sub-clinical L. braziliensis infection and, together with uninfected individuals, will compose the controls we will recruit for our studies. After the conclusion of these studies we should have identified the molecules from Notch signaling that contributes from inflammatory response in CL and ML.

描述（由申请方提供）：巴西利什曼原虫感染可导致炎症性临床形式的疾病，皮肤（CL）和粘膜利什曼病（ML）。来自这些个体的外周血单核细胞（PBMC）响应于可溶性利什曼原虫抗原分泌高水平的IFN-γ和TNF-α以及低水平的IL-10。这些患者的病变由单核细胞浸润组成，很少观察到寄生虫。尽管控制了寄生虫繁殖，但免疫病理学仍然存在，并且尝试使用重组IL-10或单克隆抗体抗IL-12和抗IL-15在体外调节炎症未能下调这些患者PBMC中的IFN-γ产生，这表明另一种免疫应答调节机制可能有助于CL和ML的发病机制。已经报道了Notch信号传导在淋巴细胞分化、增殖和细胞因子产生中的作用。Notch配体Delta 4在树突状细胞（DC）中的表达显示出协调Th 1细胞的分化，并且最近已经显示出Toll样受体配体诱导的DC和单核细胞活化也依赖于Notch信号传导。我们的初步数据显示，使用γ分泌酶抑制剂破坏Notch信号传导可以减少CL患者中利什曼原虫抗原诱导的IFN-γ产生。此外，我们的数据表明，人单核细胞分化为CD 16+（促炎单核细胞）依赖于γ分泌酶活性。在本提案中，我们试图鉴定参与Notch信号传导（Delta和Jagged）的分子，所述Notch信号传导参与CL和ML个体中炎症反应的产生和维持。患者和对照将从L.巴西东北部Corte de佩德拉的巴西丝虫传播流行区。在该流行区，平均每年发生1000例CL病例和40例ML病例，我们的研究组在该地区进行了近三十年的临床和免疫学研究。在科尔特德佩德拉的地方病区，我们还发现15%的人群有利什曼原虫抗原皮试阳性，无症状或病史。已知这些个体患有亚临床L。巴西人感染，并与未感染的个体一起，将组成我们将招募用于我们研究的对照。在这些研究结束后，我们应该已经确定了来自Notch信号传导的分子，这些分子有助于CL和ML的炎症反应。

项目成果

Inhibition of gamma-secretase activity without interfering in Notch signalling decreases inflammatory response in patients with cutaneous leishmaniasis.

• DOI: 10.1080/22221751.2021.1932608
• 发表时间: 2021-12
• 期刊: Emerging microbes & infections
• 影响因子: 13.2
• 作者: Nascimento MT;Franca M;Carvalho AM;Amorim CF;Peixoto F;Beiting D;Scott P;Carvalho EM;Carvalho LP
• 通讯作者: Carvalho LP