Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections.
Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections.
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DOI：
10.1371/journal.ppat.1001052
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发表时间：
2010-08-19
期刊：
影响因子：
6.7
通讯作者：
Brenchley JM
中科院分区：
文献类型：
--
作者：
Estes JD;Harris LD;Klatt NR;Tabb B;Pittaluga S;Paiardini M;Barclay GR;Smedley J;Pung R;Oliveira KM;Hirsch VM;Silvestri G;Douek DC;Miller CJ;Haase AT;Lifson J;Brenchley JM
HIV感染的慢性期以免疫系统的病理激活为标志，其程度比血浆病毒载量或CD 4 + T细胞计数更好地预测疾病进展。最近，微生物产物从胃肠道的易位被认为是这种免疫激活的潜在原因，这是基于间接证据，包括在慢性HIV感染的人或SIV感染的亚洲猕猴的血浆中检测到微生物产物和特异性免疫应答。我们分析了SIV感染恒河猴（RM）的组织，以提供直接的原位证据，证明微生物成分从肠腔转移到固有层，并转移到引流和外周淋巴结和肝脏，同时伴有受影响组织的局部免疫反应。在慢性SIV感染的RM中，这种易位与胃肠道（GI）上皮屏障完整性的破坏和固有层巨噬细胞明显不能有效吞噬易位的微生物成分有关。相比之下，在SIV感染的慢性阶段，我们没有发现上皮屏障破坏的证据，没有增加微生物易位，也没有病理性免疫激活。由于免疫激活是进行性HIV/SIV感染慢性期的特征，这些发现表明，来自胃肠道的微生物易位增加，超过清除易位微生物成分的能力，有助于驱动病理性免疫激活。新的治疗方法，以抑制微生物易位和/或减弱慢性免疫激活艾滋病毒感染者可能补充治疗旨在直接抑制病毒复制。免疫系统的持续激活是慢性HIV/SIV感染的标志，并且比血浆病毒载量或CD 4 + T细胞计数更好地预测疾病进展。虽然慢性感染期间免疫激活的原因可能是多因素的，但最近的工作表明微生物易位与免疫激活有关。然而，直接的，组织水平的体内易位的证据和潜在的机制仍然不清楚。在这里，我们寻求直接的体内证据易位，并了解的时间和潜在的机制。我们发现，在RM中，微生物易位开始于SIV感染的晚期急性期，并在慢性感染期间逐渐增加，并与胃肠道的结构损伤相关。我们进一步发现，免疫激活与微生物易位以及肠道巨噬细胞相对不能结合/吞噬易位的微生物产物在时间上和因果上相关。然而，在SIV感染的白眉猴中，没有观察到上皮屏障破坏的证据，也没有观察到微生物易位或慢性免疫激活的增加。我们的研究结果提供了直接的证据，在体内微生物易位，加上早期和进行性肠上皮损伤，并最终损害巨噬细胞清除与微生物产品的传播和全身免疫激活。
The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4+ T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication. Persistent activation of the immune system is a hallmark of chronic HIV/SIV infections and predicts disease progression better than either plasma viral load or CD4+ T cell count. While the causes of immune activation during chronic infection are likely multifactorial, recent work has shown that microbial translocation is associated with immune activation. However, direct, tissue level in vivo evidence of translocation and the underlying mechanisms remain unclear. Here, we sought direct in vivo evidence of translocation, and an understanding of the timing and the underlying mechanisms. We found that in RMs, microbial translocation begins during the late acute phase of SIV infection and increases progressively during chronic infection and is associated with structural damage of the GI tract. We further discovered that immune activation is temporally and causally related to microbial translocation and by the relative inability of intestinal macrophages to bind/phagocytose translocated microbial products. In SIV-infected sooty mangabeys, however, no evidence of epithelial barrier breakdown, nor increased microbial translocation or chronic immune activation were observed. Our results provide direct evidence for microbial translocation in vivo, coupled with early and progressive intestinal epithelial damage, and eventual impairment of macrophage clearance associated with dissemination of microbial products and systemic immune activation.
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