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）项目的目标是通过与马里、乌干达和印度这三个发展中国家的科学家和医生建立伙伴关系，在传染病高负担领域制定一个持续的研究项目。ICER方案的既定目标是与国内科学家合作，解决主要的地方病问题，并促进疟疾、艾滋病毒、丝虫病感染和结核病等领域的研究。希望是通过提供长期承诺来建立可持续的研究项目，从而使困难的研究挑战得以解决，而且重要的是，培训当地科学家，使他们为未来应对新出现和再出现的传染病做好准备。