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）是一种潜在的免疫调节核外侧，它限制了由于 炎。 ADO由代谢化的细胞表面过酶（CD39/CD73）的作用产生 三磷酸腺苷（ATP）或烟酰胺腺苷二核苷酸（NAD+）单磷酸腺苷 （放大器）然后进入ADO。我们的NHP研究表明，在SIV感染后，肠道组织中的ADO水平 在致病感染模型中较低（辫状猕猴，PTM；会出现严重的肠道功能障碍 在SIV感染上的全身性膨胀）比非人病感染模型（非洲绿猴， AGM；在SIV感染后保持IA/INFR的完整肠道屏障和基线水平）。不同的 CD39/CD73在粘膜Tregs上的表达和这些物种中的ADO水平与不同 对SIV的炎症反应支持ADO在控制非致病性SIV感染中IA/INFR的关键作用。 ADO水平的变化主要发生在肠道中，表明ADO途径可能涉及 在发展与SIV相关的肠道功能障碍的AGM中。这些发现强烈支持了重要的 ADO途径参与SIV/HIV相关肠道功能障碍的发病机理，并表明更多 旨在利用病毒复制粘膜部位的ADO途径的重点研究。在这个 项目，我们将直接检验以下假设：ADO信号通路在调制该假设中起着关键作用 SIV/HIV感染后的炎症性肠粘膜环境，旨在增加ADO的干预措施 在致病性SIV感染模型中产生。我们将施用HIF-1α-羟基羟化酶抑制剂 roxadustat以长期感染了SIV感染的NHP，并评估其对肠道完整性和关键参数的影响 SIV发病机理。我们的目标是评估增加ADO信号对（i）减轻肠道的影响 功能障碍和全身性膨胀和（II）病毒储层。这些创新的实验将直接探测新的 调节性炎症途径，使我们能够破译负责HIV/SIV相关的机制 肠功能障碍。因此，我们的研究将为旨在保存肠道完整性的未来治疗策略提供信息 控制剩余的IA/Infl的控制是多种合并症的根本原因。最后，如果成功，我们的 实验可以直接翻译为一种新的治疗策略，以减轻与SIV/HIV相关的肠道功能障碍。