Probing the role of adenosine pathway in SIV pathogenesis

探讨腺苷途径在 SIV 发病机制中的作用

• 批准号: 10760676
• 负责人: Ivona Vasile Pandrea
• 金额: $ 79.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760676
• 关键词: Abbreviations; Address; Adenosine; Adenosine Kinase; Adenosine Monophosphate; Adenosine Triphosphate; African Green Monkey; Biological Assay; Biological Markers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell surface; Characteristics; Chronic; Circulation; Clinical; DNA; Data; Development; Dipyridamole; Down-Regulation; Environment; Enzymes; Excision; Female; Frequencies; Functional disorder; Future; Gut Mucosa; HIV; HIV Infections; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Inosine; Intervention; Intestines; Laboratories; Liquid Chromatography; Macaca nemestrina; Modeling; Mucous Membrane; Nicotinamide adenine dinucleotide; Nucleosides; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Play; Prevalence; Procollagen-Proline Dioxygenase; Production; Prognosis; Purinergic P1 Receptors; Regulatory T-Lymphocyte; Residual state; Role; SIV; Signal Pathway; Signal Transduction; Source; T cell reconstitution; T-Cell Activation; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Up-Regulation; Viral reservoir; Viremia; Virus Replication; adaptive immune response; adenosine deaminase; adenosine transporter; antiretroviral therapy; chronic infection; comorbidity; ecto-nucleotidase; experimental study; extracellular; gut health; immune activation; immunoregulation; improved; inflammatory modulation; inhibitor; innovation; male; microbial; microbial products; mucosal site; new therapeutic target; nonhuman primate; novel therapeutic intervention; peripheral blood; preservation; prevent; systemic inflammatory response; trend

Extracellular adenosine (ADO) is a potent immunoregulatory nucleoside that limits tissue damage due to inflammation. ADO is produced by the action of cell surface ectoenzymes (CD39/CD73) that metabolize adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD+) into adenosine monophosphate (AMP) and then into ADO. Our NHP studies showed that, upon SIV infection, the levels of ADO in the gut tissues are lower in models of pathogenic infection (pigtailed macaques, PTMs; which develops severe gut dysfunction and systemic INFL upon the SIV infection) than in models of nonpathogenic infection (African green monkeys, AGMs; which maintain an intact gut barrier and baseline levels of IA/INFL upon SIV infection). The different CD39/CD73 expression on mucosal Tregs and contrasting ADO levels in these species with divergent inflammatory responses to SIV support a key role of ADO in controlling IA/INFL in nonpathogenic SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing the AGMs from developing SIV-related gut dysfunction. These findings strongly support a significant involvement of the ADO pathway in the pathogenesis of SIV/HIV related gut dysfunction and indicate that more focused studies aimed to harness the ADO pathway at mucosal sites of viral replication are needed. In this project, we will directly test the hypothesis that the ADO signaling pathway plays a pivotal role in modulating the inflammatory gut mucosal environment after SIV/HIV infection, through an intervention aimed at increasing ADO production in a model of pathogenic SIV infection. We will administer the HIF-1α prolyl-hydroxylase inhibitor Roxadustat to chronically SIV-infected NHPs and assess its impact on the gut integrity and on key parameters of SIV pathogenesis. Our objectives are to assess the impact of increasing ADO signaling on (i) alleviating gut dysfunction and systemic INFL and (ii) virus reservoirs. These innovative experiments will directly probe a new regulatory inflammatory pathway, enabling us to decipher the mechanisms responsible for the HIV/SIV-related gut dysfunction. As such, our studies will inform future therapeutic strategies aimed at preservation of gut integrity and control of residual IA/INFL that are the root causes of multiple comorbidities. Finally, if successful, our experiments may be directly translated as a new therapeutic strategy to alleviate SIV/HIV-related gut dysfunction.

细胞外腺苷 (ADO) 是一种有效的免疫调节核苷，可限制由于 ADO 是由细胞表面代谢酶 (CD39/CD73) 的作用产生的。 三磷酸腺苷 (ATP) 或烟酰胺腺嘌呤二核苷酸 (NAD+) 转化为单磷酸腺苷 (AMP)，然后转化为 ADO。我们的 NHP 研究表明，SIV 感染后，肠道组织中的 ADO 水平会升高。 在病原性感染模型（猪尾猴，PTMs；会产生严重的肠道功能障碍）中较低 和 SIV 感染后的全身性 INFL）高于非病原性感染模型（非洲绿猴、 AGM；在 SIV 感染后维持完整的肠道屏障和 IA/INFL 基线水平）。 这些物种中粘膜 Tregs 上的 CD39/CD73 表达和 ADO 水平对比 对 SIV 的炎症反应支持 ADO 在控制非致病性 SIV 感染中的 IA/INFL 中发挥关键作用。 ADO 水平的变化主要发生在肠道中，表明 ADO 途径可能参与其中 这些发现有力地支持了 AGM 免受 SIV 相关肠道功能障碍的影响。 ADO 途径参与 SIV/HIV 相关肠道功能障碍的发病机制，并表明更多 需要开展旨在利用病毒复制粘膜位点的 ADO 途径的重点研究。 项目中，我们将直接检验 ADO 信号通路在调节 通过旨在增加 ADO 的干预措施，改善 SIV/HIV 感染后的炎症性肠粘膜环境 我们将在致病性 SIV 感染模型中施用 HIF-1α 脯氨酰羟化酶抑制剂。 Roxadustat 对慢性 SIV 感染的 NHP 进行治疗并评估其对肠道完整性和关键参数的影响 我们的目标是评估增加 ADO 信号传导对 (i) 缓解肠道的影响。 功能障碍和系统性 INFL 以及 (ii) 病毒储存库。这些创新实验将直接探测新的病毒库。 调节性炎症途径，使我们能够破译与 HIV/SIV 相关的机制 因此，我们的研究将为未来旨在保护肠道完整性的治疗策略提供信息。 以及控制残留 IA/INFL，这是多种合并症的根本原因。 实验可以直接转化为缓解 SIV/HIV 相关肠道功能障碍的新治疗策略。