HIV and pathogenic SIV infection are characterized by mucosal dysfunction including epithelial barrier damage, loss of Th17 cells, neutrophil infiltration, and microbial translocation with accompanying inflammation. However, it is unclear how and when these contributing factors occur relative to one another. In order to determine whether any of these features initiates the cycle of damage, we longitudinally evaluated the kinetics of mucosal and systemic T-cell activation, microbial translocation, and Th17 cell and neutrophil frequencies following intrarectal SIV infection of rhesus macaques. We additionally assessed the colon proteome to elucidate molecular pathways altered early after infection. We demonstrate increased T-cell activation (HLA-DR+) beginning 3-14 days post-SIV challenge, reduced peripheral zonulin 3-14 days post-SIV, and evidence of microbial translocation 14 days post-SIV. The onset of mucosal dysfunction preceded peripheral and mucosal Th17 depletion, which occurred 14-28 days post-SIV, and gut neutrophil accumulation was not observed. Proteins involved in epithelial structure were downregulated 3 days post-SIV followed by an upregulation of immune proteins 14 days post-SIV. These data demonstrate that immune perturbations such as Th17 loss and neutrophil infiltration occur after alterations to epithelial structural protein pathways, suggesting that epithelial damage occurs prior to widespread immune dysfunction.

中文翻译：

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SIV 感染时，肠道损伤先于粘膜免疫功能障碍。


HIV 和致病性 SIV 感染的特征是粘膜功能障碍，包括上皮屏障损伤、Th17 细胞丢失、中性粒细胞浸润以及伴随炎症的微生物易位。然而，目前尚不清楚这些影响因素如何以及何时相对彼此发生。为了确定这些特征是否会引发损伤周期，我们纵向评估了恒河猴直肠内 SIV 感染后粘膜和全身 T 细胞激活、微生物易位以及 Th17 细胞和中性粒细胞频率的动力学。我们还评估了结肠蛋白质组，以阐明感染后早期改变的分子途径。我们证明了 SIV 攻击后 3-14 天开始 T 细胞活化 (HLA-DR+) 增加，SIV 攻击后 3-14 天外周连蛋白减少，以及 SIV 后 14 天微生物易位的证据。粘膜功能障碍发生在外周和粘膜 Th17 耗竭之前，发生在 SIV 后 14-28 天，并且没有观察到肠道中性粒细胞积聚。参与上皮结构的蛋白质在 SIV 后 3 天下调，随后免疫蛋白在 SIV 后 14 天上调。这些数据表明，Th17 丢失和中性粒细胞浸润等免疫扰动发生在上皮结构蛋白途径改变之后，表明上皮损伤发生在广泛的免疫功能障碍之前。