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Regulation of Chronic Viral Infections

Regulation of Chronic Viral Infections
慢性病毒感染的调节
批准号:
9319620
负责人:
Linda Mac Pherson Bradley
金额:
$48.75万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-09-05 至 2019-08-31

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中文摘要
翻译
描述(由申请人提供):该项目的目标是确定粘附受体PSGL-1 (p -选择素糖蛋白-1)调节慢性LCMV感染的机制,并评估靶向该受体是否代表治疗慢性病毒感染的临床转化方法。全世界有超过5亿人感染艾滋病毒、丙型肝炎病毒和乙型肝炎病毒,慢性病毒是一个重大的全球卫生问题。小鼠慢性LCMV感染模型已被广泛证明与人类慢性感染具有临床相关性。尽管许多抗病毒化合物和生物制剂可以抑制病毒复制,但目前的治疗方法与显著的毒性和/或免疫病理有关。因此,开发治疗这些疾病的新靶点至关重要
英文摘要
DESCRIPTION (provided by applicant): The goal of this project is to identify mechanisms by which the adhesion receptor, PSGL-1 (P-selectin glycoprotein-1) regulates the establishment of a chronic LCMV infection and to assess whether targeting this receptor represents a clinically translational approach to treating chronic viral infections. With more than 500 million people infected with HIV, HCV, and HBV worldwide, chronic viruses represent a major global health problem. The murine model of chronic LCMV infection has been widely demonstrated to have clinical relevance to human chronic infections. Although numerous anti-viral compounds and biologicals can inhibit viral replication, current therapies are associated with significant toxiciy and/or immunopathology. It is therefore critically important to develop new targets for treat these infections. Of significance, our studies suggest that ligation PSGL-1 on T cells may be a pivotal event that limits the effector T cell accumulation and leads to dysfunctional virus-specific T cell responses that underlie chronic viral infections. Our data show that the chronic LCMV virus (Clone 13/Cl 13) is unable to establish chronicity in mice that are genetically deficient in PSGL-1, a major receptor for the selectin family of adhesion molecules (P, E, and L). Instead, there are dramatic increases in the numbers of virus-specific CD8+ T cells, deletion of virus-specific T cells is curtailed, and persisting anti-viral T cells fail to develop the exhausted phenotype characterized by sequential loss of effector functions. Virus-specific T cells from PSGL-1 KO mice express greatly reduced levels of immune inhibitory receptors, resulting in enhanced CD8+ T cell functional responses during chronic infection. In addition, the absence of PSGL-1 also supports enhanced virus-specific CD4+ T cell responses to LCMV Cl 13. Most notably, the preservation T cell functionality is associated with viral clearance and severe immunopathology, highlighting a critical function for PSGL-1 as an immune regulator during chronic infection. The data show that there is a broad impact of PSGL-1 on T cell chronic anti-viral responses and support the hypothesis that PSGL-1 is a previously unknown key to negative regulation of T cell immune function. On the basis of our findings we propose to investigate the mechanisms engaged by PSGL-1 to limit anti-viral immunity and explore therapeutic approaches to target this receptor to enhance anti-viral effector T cell responses.
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Regulation of CD4+ T cell responses during chronic viral infection
Regulation of CD4+ T Cell Responses During Chronic Viral Infection
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