PDF(Pubmed)
Abstract：
Brucella abortus (Ba) is a pathogen that survives inside macrophages. Despite being its preferential niche, Ba infects other cells, as shown by the multiple signs and symptoms humans present. This pathogen can evade our immune system. Ba displays a mechanism of down-modulating MHC-I on monocytes/macrophages in the presence of IFN-γ (when Th1 response is triggered) without altering the total expression of MHC-I. The retained MHC-I proteins are located within the Golgi Apparatus (GA). The RNA of Ba is one of the PAMPs that trigger this phenomenon. However, we acknowledged whether this event could be triggered in other cells relevant during Ba infection. Here, we demonstrate that Ba RNA reduced the surface expression of MHC-I induced by IFN-γ in the human bronchial epithelium (Calu-6), the human alveolar epithelium (A-549) and the endothelial microvasculature (HMEC) cell lines. In Calu-6 and HMEC cells, Ba RNA induces the retention of MHC-I in the GA. This phenomenon was not observed in A-549 cells. We then evaluated the effect of Ba RNA on the secretion of IL-8, IL-6 and MCP-1, key cytokines in Ba infection. Contrary to our expectations, HMEC, Calu-6 and A-549 cells treated with Ba RNA had higher IL-8 and IL-6 levels compared to untreated cells. In addition, we showed that Ba RNA down-modulates the MHC-I surface expression induced by IFN-γ on human monocytes/macrophages via the pathway of the Epidermal Growth Factor Receptor (EGFR). So, cells were stimulated with an EGFR ligand-blocking antibody (Cetuximab) and Ba RNA. Neutralization of the EGFR to some extent reversed the down-modulation of MHC-I mediated by Ba RNA in HMEC and A-549 cells. In conclusion, this is the first study exploring a central immune evasion strategy, such as the downregulation of MHC-I surface expression, beyond monocytes and could shed light on how it persists effectively within the host, enduring unseen and escaping CD8+ T cell surveillance.
摘要：
流产布鲁氏菌（Ba）是一种在巨噬细胞内存活的病原体。尽管是它的优先利基，Ba感染其他细胞，如人类存在的多种体征和症状所示。这种病原体可以逃避我们的免疫系统。Ba显示在IFN-γ存在下（当触发Th1反应时）下调单核细胞/巨噬细胞上MHC-I的机制，而不改变MHC-I的总表达。保留的MHC-I蛋白位于高尔基体(GA)内。Ba的RNA是引发这种现象的PAMPs之一。然而,我们确认是否可以在Ba感染期间相关的其他细胞中触发此事件.这里,我们证明BaRNA降低了IFN-γ诱导的人支气管上皮（Calu-6）中MHC-I的表面表达，人肺泡上皮(A-549)和内皮微脉管系统(HMEC)细胞系。在Calu-6和HMEC细胞中，BaRNA诱导MHC-I在GA中的保留。在A-549细胞中未观察到这种现象。然后，我们评估了BaRNA对Ba感染中关键细胞因子IL-8，IL-6和MCP-1分泌的影响。与我们的期望相反,HMEC,与未处理的细胞相比,用BaRNA处理的Calu-6和A-549细胞具有更高的IL-8和IL-6水平。此外,我们发现BaRNA通过表皮生长因子受体（EGFR）途径下调IFN-γ诱导的人单核细胞/巨噬细胞MHC-I表面表达。所以,用EGFR配体阻断抗体(西妥昔单抗)和BaRNA刺激细胞.EGFR的中和在一定程度上逆转了HMEC和A-549细胞中由BaRNA介导的MHC-I的下调。总之,这是第一项探索中央免疫逃避策略的研究，如MHC-I表面表达的下调，超越单核细胞，可以揭示它如何在宿主体内有效地持续存在，忍受看不见和逃避CD8+T细胞监测。
