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，可限制因 发炎。ADO是由代谢的细胞表面胞外酶(CD39/CD73)作用产生的 三磷酸腺苷(ATP)或烟酰胺腺嘌呤二核苷酸(NAD+)转化为一磷酸腺苷 (AMP)，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 在病原性感染模型(辫尾猕猴，PTM；会发展为严重的肠道功能障碍)中较低 和全身感染)而不是在非致病性感染模型中(非洲绿猴， 在SIV感染时维持完好的肠道屏障和IA/INFL基线水平的疫苗疫苗)。不同的 CD39/CD73在不同物种粘膜树突上的表达及ADO水平的比较 对SIV的炎症反应支持ADO在非致病性SIV感染中控制IA/INFL的关键作用。 ADO水平的变化主要发生在肠道，这表明ADO途径可能参与其中 避免股东大会出现SIV相关的肠道功能障碍。这些发现有力地支持了一个重要的 ADO通路在SIV/HIV相关性肠道功能障碍发病机制中的作用 需要有针对性的研究，目的是在病毒复制的粘膜部位利用ADO途径。在这 项目中，我们将直接检验ADO信号通路在调节细胞周期中起关键作用的假设 SIV/HIV感染后的炎性肠粘膜环境，通过旨在增加ADO的干预 在致病性SIV感染模型中产生。我们将使用HIF-1α脯氨酸羟基酶抑制剂 Roxadustat用于慢性SIV感染的NHP，并评估其对肠道完整性和关键参数的影响 SIV的致病机制。我们的目标是评估增加ADO信号对(I)缓解肠道损伤的影响 功能障碍和全身性脑梗塞；(Ii)病毒库。这些创新的实验将直接探索一种新的 调控炎症途径，使我们能够破译与HIV/SIV相关的机制 肠道功能障碍。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参考。 以及控制残留的IA/INFL，这是多种并存的根本原因。最后，如果成功，我们的 实验可以直接转化为一种新的治疗策略，以缓解SIV/HIV相关的肠道功能障碍。