TRANSCRIPTOME PROFILING OF THE INTESTINAL LAMINA PROPRIA IN SIV INFECTION

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 胃肠道（GI）是艾滋病发病的关键，因为它是病毒传播的主要部位，也是病毒复制和CD 4 + T细胞破坏的主要部位。因此，胃肠道疾病，HIV/SIV感染的主要并发症，可促进管腔细菌产物的移位，引起局部/全身免疫激活，导致AIDS进展。为了更好地了解胃肠道疾病的分子机制，我们分析了全球基因表达谱顺序在肠道相同的动物之前，并在21和90天后SIV感染（PI）。我们通过获得连续的肠切除术和分别检查不同的粘膜成分（上皮内淋巴细胞，固有层淋巴细胞[LPL]，上皮和纤维血管基质）来最大限度地收集信息。在这里，我们报告有关LPL的数据。大幅增加（在免疫防御/炎症、细胞粘附/迁移、细胞信号传导和细胞分裂/分化基因中，在21和90 d PI观察到1.7倍）。与JAK-STAT通路（IL 21、IL 12 R、STAT 5A、IL 10、SOCS 1）和T细胞活化（NFATc 1）相关的基因在PI 21天时显著上调。在感染后21天显著下调的基因包括IL 17 D/IL 27和IL 28 B/IFN 3，活化诱导的胞苷脱氨酶和大约43个调节氧化磷酸化的基因，氧化磷酸化是与T细胞活化相关的关键代谢转变。90 d转录组显示炎症（CXCL 11，几丁质酶-1，JNK 3），免疫激活（semaphorin 7A），B细胞功能障碍（CD 70），肠道微生物易位（LBP）和线粒体抗病毒信号（NLRX 1）基因的进一步增强。在90 d PI时，CD 28、CD 4、CD 86、NFATc 1、TLR 8、IL 8和CCL 18的表达减少表明免疫细胞功能进一步恶化。这些转录特征为HIV/SIV诱导的胃肠道疾病的分子病理学提供了重要的新细节，并代表了未来治疗的有希望的靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4+ T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of luminal bacterial products causing localized/systemic immune activation leading to AIDS progression. To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). We maximized information gathering by obtaining sequential intestinal resections and examining distinct mucosal components (intraepithelial lymphocytes, lamina propria lymphocytes [LPL], epithelium and fibrovascular stroma) separately. Here we report data pertaining to the LPL. A significant increase (¿1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFN¿3, activation induced cytidine deaminase and approximately 43 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (semaphorin7A), B-cell dysfunction (CD70), intestinal microbial translocation (LBP) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, NFATc1, TLR8, IL8 and CCL18 at 90d PI suggests further deterioration of immune cell function. The transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and represent promising targets for future therapy.