India International Center for Excellence in Research

印度国际卓越研究中心

• 批准号: 7964701
• 负责人: Thomas Nutman
• 金额: $ 121.39万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/7964701
• 关键词: Address; Antigens; Area; C-Type Lectins; CCL18 gene; CD4 Positive T Lymphocytes; Cells; Communicable Diseases; Country; Cytotoxic T-Lymphocyte-Associated Protein 4; Developed Countries; Developing Countries; Development; Down-Regulation; Elephantiasis; Emerging Communicable Diseases; Endemic Diseases; Exhibits; Family; Filarial Elephantiases; Fostering; Future; Galactose; Goals; HIV; Hand; Helminths; Human; Hydrocele; Hypersensitivity skin testing; Immune response; India; Individual; Infection; Institution; Integration Host Factors; Interferons; Interleukin-17; Legal patent; Ligands; Lymphatic; Lymphedema; Malaria; Mali; Mediating; Medical Research; Mycobacterium tuberculosis; Nitric Oxide Synthase; Parasites; Pathogenesis; Pathology; Patients; Pattern; Phenotype; Physicians; Production; Research; Role; Scientist; Site; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Training; Tuberculin Test; Tuberculosis; Uganda; Up-Regulation; arginase; chemokine; cytokine; filaria; in vivo; interleukin-23; international center; macrophage; mannose receptor; monocyte; mycobacterial; pathogen; programs; resistin; response

The goal of the ICER (International Centers for Excellence in Research) program is to develop a sustained research program in areas of high infectious disease burden through partnerships with scientists and physicians in developing countries in three countries, Mali, Uganda, and India. The stated goal of the ICER program was to partner with in-country scientists to address major endemic diseases and foster research in areas such as malaria, HIV, filarial infections and tuberculosis. The hope was to build sustainable research programs by providing a long-term commitment, thus allowing difficult research challenges to be addressed, and, importantly, to train local scientists so that they are prepared to tackle emerging and re-emerging infectious diseases into the future. By the expression patterns of arginase 1 (Arg 1)/NO synthase 2 (Nos2), alternative activation markers, and cytokines in monocytes from filaria infected (INF) and uninfected (UN) individuals ex vivo and in response to filarial antigen, we have shown that monocytes from INF exhibit significantly diminished expression of Nos2 and significantly enhanced expression of Arg 1. These changes were associated with significantly increased expression of resistin, mannose receptor C type 1 (MRC 1), macrophage galactose type C lectin (MGL), and chemokine ligand 18 (CCL18). In response to BmA, purified monocytes from infected individuals also expressed significantly lower levels of IL 12 and IL 18 but, in contrast, exhibited significantly higher levels of expression of TGFβ, IL 10, and SOCS 1. Inhibition of arginase resulted in significantly diminished expression of resistin, MRC 1, MGL, and CCL18 as well as significantly enhanced expression of Nos2, IL 12, and IL 18 suggesting that arginase is involved in the establishment of the alternatively activated phenotype and immunoregulatory function of monocytes. Thus, patent human filarial infection is associated with the expansion of monocytes characterized by an arginase dependent 'alternatively' activated immunoregulatory phenotype. As lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele and elephantiasis we have elucidated the role of CD4+ T cell subsets in the development of lymphatic pathology by examining, of cytokines in individuals with filarial lymphedema and compared them to responses from asymptomatic, infected individuals. Parasite antigen but not control antigen induced significantly higher production of the prototypical Th1-type cytokines IFNg and TNFa in patients with lymphedema compared to asymptomatic individuals. Interestingly, the expression of the Th17 family of cytokines IL-17A, IL-17F, IL-21 and IL-23 was also significantly upregulated by BmA stimulation in lymphedema patients. On the other hand, expression of natural regulatory T cell markers - Foxp3 and GITR - was significantly impaired in lymphedema patients. While we did not find any significant differences in the expression of TLRs following parasite Ag stimulation, BmA induced significant upregulation of Nod1 and Nod2 in patients with lymphedema. Our findings implicate increased Th1/Th17 responses, decreased Tregs as well as NLR in the pathogenesis of filarial lymphedema. Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of a tissue invasive helminth may modulate the predominant Th1 (IFN γ mediated) response needed to control Mycobacterium tuberculosis (Mtb) infection. By analyzing the cellular responses to mycobacterial antigens (in patients with latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with Mtb significantly diminishes Mtb specific Th1 (IL 12/IFN γ) and Th17 (IL 23/IL 17) responses that was related to increased expression of CTLA 4 and PD 1. Blockade of CTLA 4 restored production of both IFN γ and IL 17, while PD 1 blockade restored IFN γ production only. Thus, coincident filarial infection exerted a profound inhibitory effect on protective mycobacterial-specific Th1 and Th17 responses in latent tuberculosis and suggests a mechanism by which concomitant filarial (and other systemic helminth) infections predispose to the development of active tuberculosis in humans. The factors governing latency in tuberculosis are not well understood, but appear to include pathogen and host factors. To study the role of Th1, Th2 and Th17 responses in latent tuberculosis, we examined the immune responses of those tuberculin skin test positive (PPD+; latent TB) or skin test negative (PPD- healthy contacts) individuals to PPD, Mtb culture filtrate antigen (Mtb CFA) or anti-CD3. While PPD- and Mtb CFA-specific Th1 and Th2 cytokines were not significantly different between the two groups, Th17 cytokines IL-17 and IL23 were significantly decreased in PPD+ individuals. This cytokine modulation is associated with significantly increased expression of CTLA-4 as well as Foxp3 in response to PPD and Mtb CFA. While CTLA-4 blockade had no significant effect on IL-17 and IL-23 production of PPD+ individuals, depletion of Tregs significantly increased the production of both cytokines. Thus, latent Tb is characterized by an increased activity of Tregs and a coincident downregulation of Th17 cells.

ICER(国际卓越研究中心)计划的目标是通过与马里、乌干达和印度三个发展中国家的科学家和医生合作，在传染病负担较高的领域制定持续的研究计划。ICER计划的既定目标是与国内科学家合作，解决主要地方性疾病，并促进疟疾、艾滋病毒、丝虫感染和结核病等领域的研究。希望通过提供长期承诺来建立可持续的研究计划，从而使困难的研究挑战得以解决，更重要的是，培训当地科学家，使他们为未来应对新出现和再次出现的传染病做好准备。 通过体外丝虫感染和未感染丝虫患者单核细胞精氨酸酶1(Arg 1)/一氧化氮合成酶2(NOS2)、交替激活标志物和细胞因子的表达模式，我们发现INF的单核细胞NOS2的表达显著降低，而Arg1的表达显著增强。这些变化与抵抗素、甘露糖受体C型(MRC1)、巨噬细胞C型半乳糖凝集素(MGL)和趋化因子配体18(CCL18)的表达显著增加有关。作为对BMA的反应，来自感染者的纯化单核细胞表达IL 12和IL 18的水平也显著降低，但相反地，表现出显著高水平的转化生长因子、IL 10和SOCS 1的表达。抑制精氨酸酶导致抵抗素、MRC1、MGL和CCL18的表达显著减少，而NOS2、IL 12和IL 18的表达显著增强，这表明精氨酸酶参与了单核细胞交替激活的表型和免疫调节功能的建立。因此，人类丝虫感染与单核细胞的扩张有关，其特征是依赖于精氨酸酶的免疫调节表型被激活。 由于淋巴丝虫病可与淋巴水肿、鞘膜积液和象皮病等严重病理的发展相关，我们通过检测丝虫病淋巴水肿患者的细胞因子，并将其与无症状的感染患者的反应进行比较，阐明了CD4+T细胞亚群在淋巴病理发展中的作用。与无症状的患者相比，寄生虫抗原而不是对照抗原诱导淋巴水肿者产生的Th1型细胞因子IFNG和TNFa显著增加。有趣的是，淋巴水肿患者Th17家族细胞因子IL-17A、IL-17F、IL-21和IL-23的表达也被BMA刺激显著上调。另一方面，淋巴水肿患者自然调节性T细胞标志物Foxp3和GITR的表达显著受损。虽然我们没有发现在寄生虫抗原刺激后TLRs的表达有任何显著差异，但BMA诱导了淋巴水肿患者Nod1和NOD2的显著上调。我们的发现提示Th1/Th17反应增加，Tregs和NLR减少在丝虫性淋巴水肿的发病机制中。 结核分枝杆菌(Mtb)和丝虫混合感染非常普遍，组织侵袭性蠕虫的存在可能调节控制结核分枝杆菌(Mtb)感染所需的主要Th1(干扰素介导)反应。通过分析细胞对分枝杆菌抗原的反应(在有或没有丝虫感染的潜伏性结核病患者中，我们能够证明丝虫感染合并结核分枝杆菌感染显著降低了与CTLA 4和PD 1表达增加有关的Mtb特异性Th1(IL 12/干扰素)和Th17(IL 23/IL 17)反应。阻断CTLA 4恢复了干扰素和IL 17的产生，而阻断PD 1仅恢复了干扰素的产生。因此，丝虫感染对潜伏期结核病中分枝杆菌特异性Th1和Th17的保护性反应产生了深刻的抑制作用，并提示了一种伴随丝虫(和其他系统性蠕虫)感染易导致人类活动性结核病发展的机制。 控制结核病潜伏期的因素还不是很清楚，但似乎包括病原体和宿主因素。为了研究Th1、Th2和Th17在潜伏性结核病中的作用，我们检测了结核菌素皮试阳性(PPD+；潜伏期TB)和皮试阴性(PPD-健康接触者)对PPD、Mtb培养滤液抗原(Mtb CFA)或抗CD3的免疫反应。PPD和Mtb CFA特异性Th1和Th2细胞因子在两组间无显著差异，而Th17细胞因子IL-17和IL23在PPD+患者中显著降低。这种细胞因子的调节与PPD和Mtb CFA反应中CTLA-4和Foxp3的表达显著增加有关。阻断CTLA-4对PPD+个体的IL-17和IL-23的产生无明显影响，而Tregs的耗竭显著增加了这两种细胞因子的产生。因此，潜伏性结核病的特征是Tregs活性增加和Th17细胞下调。