Clinical Mycology Unit, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Pathog. 2012;8(8):e1002865. doi: 10.1371/journal.ppat.1002865. Epub 2012 Aug 16.
Invasive candidiasis is the 4(th) leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1(lo) to Ccr1(high) at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1(+/+) and Ccr1(-/-) donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1(+/+) recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1(+/+) cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.
侵袭性念珠菌病是美国第四大院内血流感染的病因，尽管进行了抗真菌治疗，死亡率仍超过 40%；中性粒细胞减少是侵袭性念珠菌病后不良预后的主要危险因素。在一种模拟人类血流性侵袭性念珠菌病的致命性小鼠模型中，受感染最严重的器官是肾脏，中性粒细胞是宿主防御的主要细胞介质；然而，以前尚未确定调节中性粒细胞募集的因素。在这里，我们表明，广泛表达于白细胞上的趋化因子受体 Ccr1 缺失的小鼠，其肾脏中中性粒细胞的积累选择性受损，仅限于该模型时间过程的晚期；令人惊讶的是，这与肾功能改善和存活率提高相关，而不影响组织真菌负担。与此一致的是，来自野生型小鼠的血液和肾脏中的中性粒细胞在感染后晚期从 Ccr1(lo)转变为 Ccr1(high)，此时肾脏中产生高水平的 Ccr1 配体，并对肾脏中性粒细胞具有趋化性。此外，当将 Ccr1(+/+)和 Ccr1(-/-)供体中性粒细胞以 1∶1 的比例通过静脉内转移到 Candida 感染的 Ccr1(+/+)受体小鼠中时，中性粒细胞向肾脏的迁移明显偏向于 Ccr1(+/+)细胞。因此，中性粒细胞 Ccr1 通过介导来自血液向靶器官的中性粒细胞过度募集，放大了侵袭性念珠菌病的晚期肾脏免疫病理学，并增加了死亡率。
