Benoit Marie, Ghigo Eric, Capo Christian, Raoult Didier, Mege Jean-Louis
Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, CNRS UMR 6236, Institut Fédératif de Recherche 48, Université de la Méditerranée, Faculté de Médecine, Marseille, France.
PLoS Pathog. 2008 May 16;4(5):e1000066. doi: 10.1371/journal.ppat.1000066.
Patients with valvulopathy have the highest risk to develop infective endocarditis (IE), although the relationship between valvulopathy and IE is not clearly understood. Q fever endocarditis, an IE due to Coxiella burnetii, is accompanied by immune impairment. Patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes, as determined by the measurement of active caspases and nucleosome determination. The binding of apoptotic cells to monocytes and macrophages, the hosts of C. burnetii, may be responsible for the immune impairment observed in Q fever endocarditis. Apoptotic lymphocytes (AL) increased C. burnetii replication in monocytes and monocyte-derived macrophages in a cell-contact dependent manner, as determined by quantitative PCR and immunofluorescence. AL binding induced a M2 program in monocytes and macrophages stimulated with C. burnetii as determined by a cDNA chip containing 440 arrayed sequences and functional tests, but this program was in part different in monocytes and macrophages. While monocytes that had bound AL released high levels of IL-10 and IL-6, low levels of TNF and increased CD14 expression, macrophages that had bound AL released high levels of TGF-beta1 and expressed mannose receptor. The neutralization of IL-10 and TGF-beta1 prevented the replication of C. burnetii due to the binding of AL, suggesting that they were critically involved in bacterial replication. In contrast, the binding of necrotic cells to monocytes and macrophages led to C. burnetii killing and typical M1 polarization. Finally, interferon-gamma corrected the immune deactivation induced by apoptotic cells: it prevented the replication of C. burnetii and re-directed monocytes and macrophages toward a M1 program, which was deleterious for C. burnetii. We suggest that leukocyte apoptosis associated with valvulopathy may be critical for the pathogenesis of Q fever endocarditis by deactivating immune cells and creating a favorable environment for bacterial persistence.
患有瓣膜病的患者发生感染性心内膜炎（IE）的风险最高，尽管瓣膜病与IE之间的关系尚未完全明确。Q热心内膜炎是由伯氏考克斯体引起的一种IE，伴有免疫功能受损。通过活性半胱天冬酶的测量和核小体测定发现，患有瓣膜病的患者循环凋亡白细胞水平升高。凋亡细胞与伯氏考克斯体的宿主单核细胞和巨噬细胞的结合，可能是Q热心内膜炎中观察到的免疫功能受损的原因。通过定量PCR和免疫荧光测定，凋亡淋巴细胞（AL）以细胞接触依赖的方式增加了单核细胞和单核细胞衍生巨噬细胞中伯氏考克斯体的复制。如通过包含440个排列序列的cDNA芯片和功能测试所确定的，AL结合在受到伯氏考克斯体刺激的单核细胞和巨噬细胞中诱导了M2程序，但该程序在单核细胞和巨噬细胞中部分不同。与AL结合的单核细胞释放高水平的IL-10和IL-6，低水平的TNF并增加CD14表达，而与AL结合的巨噬细胞释放高水平的TGF-β1并表达甘露糖受体。IL-10和TGF-β1的中和由于AL的结合而阻止了伯氏考克斯体的复制，表明它们在细菌复制中起关键作用。相反，坏死细胞与单核细胞和巨噬细胞的结合导致伯氏考克斯体被杀伤和典型的M1极化。最后，干扰素-γ纠正了凋亡细胞诱导的免疫失活：它阻止了伯氏考克斯体的复制，并将单核细胞和巨噬细胞重新导向对伯氏考克斯体有害的M1程序。我们认为，与瓣膜病相关的白细胞凋亡可能通过使免疫细胞失活并为细菌持续存在创造有利环境，对Q热心内膜炎的发病机制至关重要。
