DIFFERENT TGF-BETA PROFILES IN SIVMAC AND SIVAGM INFECTION

SIVMAC 和 SIVAGM 感染中不同的 TGF-β 谱

• 批准号: 7562370
• 负责人: Ivona Vasile Pandrea
• 金额: $ 7.16万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562370
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Cercopithecus pygerythrus; Computer Retrieval of Information on Scientific Projects Database; Data; Enrollment; Funding; Grant; HIV-1; Human; Infection; Inflammation; Institution; Interferons; Interleukin-10; Macaca; Mediator of activation protein; Plasma; Polymerase Chain Reaction; Prospective Studies; Research; Research Personnel; Resources; Signal Transduction; Source; T-Cell Activation; TNF gene; Time; Transcript; Transcriptional Activation; Transforming Growth Factor beta; United States National Institutes of Health; Up-Regulation; Virus; Week; day; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-¿1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-¿1 induction persists during primary infection. We hypothesized that MACs are unable to respond to TGF-¿1 and thus cannot control virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory molecules as well as of factors involved in the TGF-¿1 signaling in SIV-infected AGMs and MACs. Levels of transcripts encoding pro- and anti-inflammatory molecules (TNF- ¿, IFN- ¿, IL-10, T-BET, GATA-3) as well as for TGF-¿1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. During primary SIVmac infection, up-regulations of TNF- ¿, IFN- ¿ and T-BET responses (days 116 p.i.) were stronger whereas IL-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 38 p.i.), a cellular mediator inhibiting the TGF-¿1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of GATA-3 but not T-BET, a longer lasting up-regulation of smad4 (days 121 p.i), a mediator enhancing TGF-¿1 signaling, and no smad7 up-regulations. Our data suggest that the inability to control virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is due to up-regulation of smad7 that inhibits early TGF-beta expression.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在非洲绿猴 (AGM) 的非致病性 SIVagm 感染中，未发现人类和猕猴 (MAC) 中 HIV-1 和 SIVmac 感染的普遍 T 细胞激活特征。我们之前已经表明，TGF-¿1、Foxp3 和 IL-10 在 SIVagm 感染后很早就被诱导。在 SIVmac 感染的 MAC 中，血浆 TGF-¿1 诱导在初次感染期间持续存在。我们假设 MAC 无法对 TGF-¿1 做出反应，因此无法控制病毒驱动的炎症。因此，我们比较了 SIV 感染的 AGM 和 MAC 中促炎分子和抗炎分子以及参与 TGF-¿1 信号传导的因子的早期表达动态。在一项招募 6 个 AGM 和 6 个 MAC 的前瞻性研究中，通过实时 PCR 跟踪编码促炎和抗炎分子（TNF-¿、IFN-¿、IL-10、T-BET、GATA-3）以及 TGF-¿1 信号传导介质（smad3、smad4、smad7）的转录物水平。在原发性 SIVmac 感染期间，与 SIVagm 感染相比，TNF-¿、IFN-¿ 和 T-BET 反应（注射后第 1-16 天）的上调更强，而 IL-10 反应延迟（注射后第 4 周）。 smad7 的上调（注射后第 3 天至 8 天）是一种抑制 TGF-β1 信号级联的细胞介质，是 SIV 感染的 MAC 的特征。在 AGM 中，我们发现 GATA-3 增加，但 T-BET 没有增加，smad4（注射后 1-21 天）（一种增强 TGF-¿1 信号传导的介质）持续上调，但没有 smad7 上调。 我们的数据表明，无法控制病毒驱动的炎症和激活 在致病性 HIV-1/SIVmac 感染过程中，smad7 的上调抑制了早期 TGF-β 的表达。