The uptake of apoptotic cells drives Coxiella burnetii replication and macrophage polarization: a model for Q fever endocarditis.
The uptake of apoptotic cells drives Coxiella burnetii replication and macrophage polarization: a model for Q fever endocarditis.
复制标题
DOI：
10.1371/journal.ppat.1000066
复制
发表时间：
2008-05-16
期刊：
影响因子：
6.7
通讯作者：
Mege JL
中科院分区：
文献类型：
--
作者：
Benoit M;Ghigo E;Capo C;Raoult D;Mege JL
瓣膜病患者发生感染性心内膜炎（IE）的风险最高，尽管瓣膜病和IE之间的关系尚不清楚。Q热心内膜炎是一种由贝氏柯克斯体引起的IE，伴有免疫功能损害。瓣膜病患者表现出循环凋亡白细胞水平升高，通过测量活性半胱天冬酶和核小体测定确定。凋亡细胞与C.贝氏体，可能是Q热心内膜炎中观察到的免疫损伤的原因。凋亡淋巴细胞（AL）增加C。如通过定量PCR和免疫荧光测定的，贝氏体在单核细胞和单核细胞衍生的巨噬细胞中以细胞接触依赖性方式复制。在C.通过包含440个阵列序列和功能测试的cDNA芯片确定了伯内特氏菌，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和增加的CD 14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的中和作用可抑制C. burnetii由于AL的结合，这表明它们在细菌复制中起关键作用。相比之下，坏死细胞与单核细胞和巨噬细胞的结合导致了C。Burnetii杀灭和典型的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C.将单核细胞和巨噬细胞重定向到M1程序，这对C.伯内特氏菌我们认为，与瓣膜病相关的白细胞凋亡可能是Q热心内膜炎的发病机制的关键，通过灭活免疫细胞和创造一个有利的环境，细菌的持久性。感染性心内膜炎（IE）是一个公共卫生问题，尽管有抗生素治疗，但仍然导致高死亡率。大多数发生IE的患者有预先存在的心脏病变，尽管IE和瓣膜病之间的关系尚不清楚。我们发现，瓣膜病患者循环中凋亡性白细胞水平升高。由于已知凋亡细胞与单核细胞和巨噬细胞的结合可抑制其炎症活性，我们假设高水平的循环凋亡白细胞可能是Q热心内膜炎中观察到的免疫损伤的原因，Q热心内膜炎是由贝氏柯克斯体（一种在单核细胞和巨噬细胞中存活的细菌）引起的IE。凋亡淋巴细胞与单核细胞和巨噬细胞的结合增加了C. burnetii通过刺激他们的抗炎反应。相反，坏死淋巴细胞与单核细胞和巨噬细胞的结合诱导C。Burnetii杀死并刺激炎症反应。干扰素-γ与C.贝氏体感染，阻止了C.单核细胞和巨噬细胞中的贝氏体通过刺激其炎症反应而结合凋亡淋巴细胞。总之，我们认为，白细胞凋亡与瓣膜病可能是Q热心内膜炎的发病机制，通过灭活免疫细胞，创造一个有利的环境，病原体的持久性。
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-β1 and expressed mannose receptor. The neutralization of IL-10 and TGF-β1 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-γ 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. Infective endocarditis (IE) is a problem of public health that still causes high mortality despite antibiotic treatments. Most of the patients who develop an IE have pre-existing cardiac lesions, although the relationship between IE and valvulopathy is not clearly understood. We showed here that patients with valvulopathy exhibited increased levels of circulating apoptotic leukocytes. As the binding of apoptotic cells to monocytes and macrophages is known to inhibit their inflammatory activity, we hypothesized that the high levels of circulating apoptotic leukocytes may be responsible for the immune impairment observed in Q fever endocarditis, an IE due to Coxiella burnetii, a bacterium that survives in monocytes and macrophages. The binding of apoptotic lymphocytes to monocytes and macrophages increased the replication of C. burnetii by stimulating their anti-inflammatory response. In contrast, the binding of necrotic lymphocytes to monocytes and macrophages induced C. burnetii killing and stimulated an inflammatory response. Interferon-γ, which is associated with the control of C. burnetii infection, prevented the replication of C. burnetii in monocytes and macrophages that have bound apoptotic lymphocytes by stimulating their inflammatory response. In conclusion, 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 pathogen persistence.
登录
查看更多内容
影响因子：
3.7
作者：
Benoit M;Fenollar F;Raoult D;Mege JL
通讯作者：
Mege JL
影响因子：
4.4
作者：
Byrne, A;Reen, DJ
通讯作者：
Reen, DJ
影响因子：
4.4
作者：
Ghigo, E;Capo, C;Mege, JL
通讯作者：
Mege, JL
影响因子：
4.6
作者：
Barker, RN;Erwig, LP;Rees, AJ
通讯作者：
Rees, AJ
DOI：
10.1073/pnas.0605331103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Erwig, Lars-Peter;McPhilips, Kathleen A.;Henson, Peter M.
通讯作者：
Henson, Peter M.