GI DYSFUNCTION IN SIV-INFECTED MACAQUES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 胃肠道疾病和炎症是HIV/SIV感染的常见后遗症。然而，导致GI功能障碍的分子机制仍不清楚。我们研究了IL-6-JAK-STAT 3通路在空肠和结肠中的调节，这些空肠和结肠在尸检时收集自10只SIV感染的腹泻猕猴（组1）、10只非SIV感染的腹泻猕猴（组2）和7只对照未感染的猕猴（组3）。第1组和第2组所有猕猴均出现慢性腹泻、消瘦和结肠炎，但第1组动物的空肠病变更频繁且更严重。与对照组相比，在所有第1组和第2组猕猴的结肠中以及仅在第1组猕猴的空肠中观察到IL-6和SOCS-3基因表达沿着组成性STAT 3活化的显著增加。此外，在结肠中，组织病理学严重程度评分与IL-6（组1和2）和SOCS-3（组2）基因表达显著相关。在空肠中，仅在第1组动物中观察到类似的相关性。磷酸化STAT 3（p-STAT 3）定位于淋巴细胞（CD 3+）和巨噬细胞（CD 68+），在第1组猕猴中表达p-STAT 3的CD 3+淋巴细胞较少。尽管高SOCS-3表达，STAT 3仍然保持组成型活性，为持续的肠道炎症和免疫激活提供了可能的解释，这可能有利于病毒复制和疾病进展。

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. Gastrointestinal disease and inflammation are common sequelae of HIV/SIV infection. Nevertheless, the molecular mechanisms that lead to GI dysfunction remain unclear. We investigated regulation of the IL-6-JAK-STAT3 pathway in jejunum and colon, collected at necropsy, from 10 SIV-infected macaques with diarrhea (group 1), 10 non-SIV infected macaques with diarrhea (group 2) and 7 control uninfected macaques (group 3). All group 1 and 2 macaques had chronic diarrhea, wasting and colitis but group 1 animals had more frequent and severe lesions in the jejunum. A significant increase in IL-6 and SOCS-3 gene expression along with constitutive STAT3 activation was observed in colon of all group 1 and 2 macaques and in jejunum of only group 1 macaques compared to controls. Further, in colon, histopathology severity scores correlated significantly with IL-6 (groups 1 & 2) and SOCS-3 (group 2) gene expression. In jejunum, a similar correlation was observed only in group 1 animals. Phosphorylated STAT3 (p-STAT3) was localized to lymphocytes (CD3+) and macrophages (CD68+) with, fewer CD3+ lymphocytes expressing p-STAT3 in group 1 macaques. Despite high SOCS-3 expression, STAT3 remained constitutively active providing a possible explanation for persistent intestinal inflammation and immune activation that may favor viral replication and disease progression.