India International Center for Excellence in Research

印度国际卓越研究中心

基本信息

批准号：
8336277
负责人：
Thomas Nutman
金额：
$ 98.25万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8336277
关键词：
Acute-Phase Proteins Address Adult Angiopoietin-1 Animals Antigen-Antibody Complex Antigens Area Asian Indian Autoimmunity Biological Markers Characteristics Child Childhood Communicable Diseases Coronary Country Cross-Sectional Studies Developing Countries Development Diabetes Mellitus Disease Elephantiasis Emerging Communicable Diseases Employee Strikes Endemic Diseases Epidemiology Extracellular Matrix Filarial Elephantiases Filariasis Fostering Functional disorder Future Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor HIV Helminths Homeostasis Human Hydrocele Immune response Incidence India Individual Infection Infection Control Inflammatory Inflammatory Response Inflammatory Response Pathway Institution Insulin-Dependent Diabetes Mellitus Interferons Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-6 Ligands Link Low Prevalence Lung Lymphangiogenesis Lymphatic Lymphedema MAP Kinase Gene MAPK3 gene Malaria Mali Mannose Binding Lectin Mannose-Binding Lectins Matrix Metalloproteinases Medical Research Monitor Morbidity - disease rate Newly Diagnosed Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Pathology Pathway interactions Patients Phosphorylation Physicians Plasma Play Population Prevalence Production Pulmonary Tuberculosis Research Research Design Role Rural Scientist Serum Serum amyloid A protein Signal Transduction Site TNF gene Tissue Inhibitor of Metalloproteinase-1 Toll-Like Receptor 2 Toll-like receptors Training Tuberculosis Uganda Up-Regulation Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor C atopy burden of illness complement system cytokine diabetic epidemiology study immunoregulation inflammatory marker interleukin-22 interleukin-23 international center mitogen-activated protein kinase p38 mycobacterial non-diabetic programs receptor function response tuberculosis immunity type I and type II diabetes

项目摘要

In the past year, we have completed a number of sudies in lymphatic filariasis, pediatric tuberculosis and the influence of filarial infection on the prevalence of Type 1 and Type 2 diabetes mellitus. In addition, we have begun two new studies to examine the role of treatment induced latency in pulmonary tuberculosis and the identification of biomarkers/morbidity markers in Lymphatic filariasis pathogenesis -- lymphatic filarial pathology including both bancroftian and brugian filariasis. Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Lymphatic filariasis (LF) pathogenesis: Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined responses to different TLR ligands in patients with lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic normal (EN) individuals. TLR 2, 7 and 9 ligands induced significantly elevated production of Th1 and other pro-inflammatory cytokines in CP patients and did so as a consequence of ERK1/2 and p38 MAP kinases phosphorylation as well as increased activation of NF-κB. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR- and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrated that in patients with lymphatic pathology (CP), TLR ligands induce significantly increased expression/production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang-1).Similarly, filarial antigens induced significantly enhanced production of VEGF-A and VEGF-C in those with CP that was associated with MAPK and NF-κB signaling. Dysregulated host inflammatory responses, lymphatic dysfunction, endothelial activation and extracellular matrix remodeling play central roles in filarial disease pathogenesis. In a large study of >200 subjects, we were able to show that plasma levels of LPS, alpha 2m,, haptoglobulin, serum amyloid A were associated with the development of lymphatic pathology as were VEGF-A and -C (p<0.0001), ANG-1, and the soluble VEGFRs (R1, R2, R3). The presence of circulating immune complexes (CIC) is a characteristic feature of human lymphatic filariasis.. Significantly increased levels of CIC and enhanced functional efficiency of the classical and Mannose-binding lectin (MBL) pathway of the complement system was observed in those with active INF compared to those with pathology associated with LF. Co-incidental diseases Epidemiological and animal studies have shown an inverse correlation between the incidence of helminth infections including LF and the incidence of atopy and autoimmunity. However, the interrelationship between LF and Type-1 and Type-2 diabetes (T1DM and T2DM, respectively) in humans is not known. Two cross-sectional studies to assess the baseline prevalence and the correlates of seropositivity of LF among diabetic subjects were undertaken in Chennai, India. The first study demonstrated asignificantly lower prevalence of LF among T1DM subjects (0%; n=200) compared to non-diabetic subjects (2.6%; n=500). More importantly, in the second study, there was a significantly lower prevalence of LF among T2DM subjects (both newly diagnosed 5.7%; n=158 and those under treatment 4.3%; n=161) compared to pre-diabetic subjects 9.1%; n=154 (p=0.0095) and non-diabetic subjects 10.4%; n=943 (p=0.0463). Among those with filarial infection, there were significantly lower filarial antigen loads among T2DM subjects compared to non-diabetic subjects (Geometric Mean of 354 U/ml in T2DM vs. 1594 U/ml in non-diabetic subjects; p=0.04). Serum levels of the pro-inflammatory cytokines - IL-6 and GM-CSF -- were significantly lower in T2DM subjects who were LF positive compared to those who were LF negative.. Thus, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished serum pro-inflammatory cytokine response in subjects with diabetes and concomitant LF. Having shown a decreased prevalence of LF among type-2 diabetic subjects which was associated with significant immunomodulation, we next assessed the baseline prevalence and the correlates of seropositivity of LF among subjects without (n=236) and with (n=217) coronary arterial disease (CAD) carried out as part of the Chennai Urban Rural Epidemiology Study (CURES). In contrast to diabetes, the prevalence of LF was not significantly different between control and CAD subjects. Serum cytokine profililing showed a moderate upregulation of inflammatory markers in LF positive compared to LF negative CAD subjects. Although a direct causal link is yet to be shown, unlike type-2 diabetes there appears to be a no association between the prevalence of LF and CAD, in the Asian Indian population. Tuberculosis Studies Type 1 cytokine responses are known to play an important role in immunity to tuberculosis (TB) in children and children are more prone to develop extrapulmonary manifestations of TB compared to adults. To identify the immune responses important both in control of infection and in extrapulmonary dissemination, we examined mycobacteriaspecific cytokine responses of children with pulmonary TB (PTB) and extrapulmonary TB (ETB) and compared them with those of healthy control children (HC). Children with active TB (PTB or ETB) showed markedly diminished production of Types 1 (IFN γ and TNF α), 2 (IL-4 and IL-13), and 17 (IL-17A, IL-21, and IL-23) associated cytokines at homeostasis as well as in response to mycobacterial antigens We next sought to identify the immune responses important in control of infection as well as extra-pulmonary dissemination in pediatric TB. Pediatric TB was shown to be characterized by elevated levels of acute phase proteins, MMPs/TIMP-1, IL-22 and TGFb suggesting that these responses may play a crucial role in protection against disease. It is also possible that these analytes may be used as biomarkers to monitor the progress of disease.

在过去的一年中，我们已经完成了许多淋巴丝虫病，小儿结核病以及丝状感染对1型和2型糖尿病患病率的影响。此外，我们已经开始了两项新的研究，以研究治疗引起的潜伏期在肺结核中的作用以及生物标志物/发病率标记中的鉴定淋巴丝虫病发病机理 - 淋巴丝状病理学，包括Bancroftian和Brugian丝虫病。淋巴丝虫病可能与在感染患者的一部分中以淋巴水肿，液能和大抗菌病的形式发展有关。淋巴丝虫病（LF）发病机理：淋巴丝虫病可能与在感染患者的一部分中以淋巴水肿，液能和大抗菌病的形式发展有关。据认为，Toll样受体（TLR）在丝状病理发展中起着重要作用。为了阐明TLR在淋巴病理学发展中的作用，我们检查了淋巴病理学（CP）患者，受感染的亚临床病理病理（INF）和未感染的特有正常患者的感染患者对不同TLR配体的反应。 TLR 2、7和9配体在CP患者中诱导TH1和其他促炎细胞因子的产生显着升高，这是由于ERK1/2和p38 MAP激酶磷酸化以及NF-κB的激活增加而导致的。为了检查TLR功能与丝状感染中淋巴管生成的发展之间的关联，我们检查了TLR和丝状抗原诱导的各种血管生成因子的表达和产生。我们证明，在淋巴病理学（CP）的患者中，TLR配体显着增加了血管内皮生长因子-A（VEGF-A），Angiopoietin-1（ANGANG-1）的表达/产生/产生。相似，丝质抗原可显着诱导的VEGGF-A和VEGFF-C与cp和cpk and-cpk and-cp的产生显着增强。失调的宿主炎症反应，淋巴功能障碍，内皮激活和细胞外基质重塑在丝状疾病发病机理中起着核心作用。在一项针对200名受试者的大型研究中，我们能够证明LPS的血浆水平，Alpha 2M，Haptoglobulin，血清淀粉样蛋白A与VEGF-A和-C（P <0.0001），ANG-1，以及可溶性Bleble Veggfrs（R1，R2，R2，R2，R3）。循环免疫复合物（CIC）的存在是人类淋巴丝虫病的一个特征。与与LF相关的患者相比，在患有活性INF的患者中观察到了补体系统的经典和甘露糖结合凝集素（MBL）途径的水平和增强的功能效率。共同疾病流行病学和动物研究表明，包括LF在内的蠕虫感染的发生率与特应性和自身免疫性的发生率之间存在逆相关性。但是，人类中LF和1型糖尿病（T1DM和T2DM）之间的相互关系尚不清楚。在印度钦奈进行了两项评估基线患病率和LF的血清阳性相关性的横断面研究。第一项研究表明，与非糖尿病受试者相比，T1DM受试者中LF的患病率降低（0％; n = 200）（2.6％; n = 500）。更重要的是，在第二项研究中，与糖尿病前受试者相比，T2DM受试者之间LF的患病率显着降低（均被新诊断为5.7％； N = 158和接受治疗的患者4.3％； N = 161）。 n = 154（p = 0.0095）和非糖尿病受试者10.4％； n = 943（p = 0.0463）。在丝状感染的患者中，与非糖尿病受试者相比，T2DM受试者之间的丝质抗原负荷明显较低（在非糖尿病受试者中，T2DM中的几何平均值为354 U/ml； P = 0.04）。与LF负相比，LF阳性的T2DM受试者的促炎细胞因子的血清水平显着降低。因此，LF和糖尿病的患病率与糖尿病的患病率显着相反，这是由血清症状症状和糖尿病的减少所反应的。在2型糖尿病受试者中显示LF的患病率降低，这与显着的免疫调节有关，我们接下来评估了LF的基线流行率和没有（n = 236）和（n = 217）冠状动脉疾病（n = 217）冠状动脉疾病（CAD）的LF的相关性（CAD）携带的一部分是Chennai urbal ryalur cur的一部分。与糖尿病相反，对照组和CAD受试者之间LF的患病率没有显着差异。与LF阴性CAD受试者相比，血清细胞因子的促进表现出LF阳性的炎症标记的中调。尽管尚未表现出直接的因果关系，但与2型糖尿病不同，亚洲印度人口中LF和CAD的患病率似乎没有关联。结核病研究已知1型细胞因子反应在儿童和儿童的结核病（TB）中起重要作用，与成人相比，儿童更容易发展结核病的外肺外表现。为了确定在控制感染和肺外传播中重要的免疫反应，我们检查了肺结核（PTB）和肺外TB（ETB）儿童的分枝杆菌特异性细胞因子反应，并将其与健康对照儿童（HC）进行了比较。活跃TB（PTB或ETB）的儿童表现出明显减少1型（IFNγ和TNFα），2（IL-4和IL-13）的产生显着减少接下来，我们试图确定对控制感染以及小儿结核病肺外传播重要的免疫反应。小儿结核病的特征是急性期蛋白水平升高，MMPS/TIMP-1，IL-22和TGFB，表明这些反应可能在保护疾病的保护中起着至关重要的作用。这些分析物也可能被用作监测疾病进展的生物标志物。