Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages.
Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages.
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DOI：
10.1371/journal.pone.0186169
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kopp BT
中科院分区：
文献类型：
--
作者：
Shrestha CL;Assani KD;Rinehardt H;Albastroiu F;Zhang S;Shell R;Amer AO;Schlesinger LS;Kopp BT
洋葱伯克霍尔德菌复合体的成员是剧毒的，多重耐药的病原体，在囊性纤维化（CF）患者的细胞内存活和复制。我们发现，由于自噬缺陷，CF巨噬细胞无法清除cenocepacia，导致持续的全身炎症和感染。CF的缺陷性自噬是通过组成性活性氧（ROS）激活谷氨酰胺转酶-2 （TG2）介导的，这导致必需的自噬起始蛋白的隔离（积累）。半胱胺是一种TG2抑制剂和蛋白酶抑制调节剂，具有恢复自噬的潜力。因此，我们试图研究半胱胺对CF巨噬细胞自噬和细菌杀伤的影响。从CF和非CF供者中分离出人外周血单核细胞来源的巨噬细胞（MDMs）和肺泡巨噬细胞。巨噬细胞感染临床分离的相关CF病原体。在没有细胞的情况下，半胱胺可以直接杀死活的绿芽胞杆菌、多角胞杆菌、铜绿假单胞菌和MRSA。此外，半胱胺治疗的CF MDMs显著降低了新冠芽孢杆菌、多角芽孢杆菌和铜绿假单胞菌的侵袭。最后，半胱胺降低CF中TG2、p62和beclin-1的积累，导致伯克霍尔德菌进入自噬体增加，巨噬细胞CFTR表达增加，ROS和IL-1β产生减少。半胱胺具有直接的抗菌生长杀伤作用，并改善人CF巨噬细胞自噬，从而增加巨噬细胞介导的细菌清除，减少炎症，减少组成性ROS的产生。因此，半胱胺可能是CF中抗生素治疗方案的有效辅助。
Members of the Burkholderia cepacia complex are virulent, multi-drug resistant pathogens that survive and replicate intracellularly in patients with cystic fibrosis (CF). We have discovered that B. cenocepacia cannot be cleared from CF macrophages due to defective autophagy, causing continued systemic inflammation and infection. Defective autophagy in CF is mediated through constitutive reactive oxygen species (ROS) activation of transglutaminase-2 (TG2), which causes the sequestration (accumulation) of essential autophagy initiating proteins. Cysteamine is a TG2 inhibitor and proteostasis regulator with the potential to restore autophagy. Therefore, we sought to examine the impact of cysteamine on CF macrophage autophagy and bacterial killing. Human peripheral blood monocyte-derived macrophages (MDMs) and alveolar macrophages were isolated from CF and non-CF donors. Macrophages were infected with clinical isolates of relevant CF pathogens. Cysteamine caused direct bacterial growth killing of live B. cenocepacia, B. multivorans, P. aeruginosa and MRSA in the absence of cells. Additionally, B. cenocepacia, B. multivorans, and P. aeruginosa invasion were significantly decreased in CF MDMs treated with cysteamine. Finally, cysteamine decreased TG2, p62, and beclin-1 accumulation in CF, leading to increased Burkholderia uptake into autophagosomes, increased macrophage CFTR expression, and decreased ROS and IL-1β production. Cysteamine has direct anti-bacterial growth killing and improves human CF macrophage autophagy resulting in increased macrophage-mediated bacterial clearance, decreased inflammation, and reduced constitutive ROS production. Thus, cysteamine may be an effective adjunct to antibiotic regimens in CF.
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DOI：
10.1016/j.bbrc.2012.06.066
发表时间：
2012-07-27
影响因子：
3.1
作者：
Kopp, Benjamin T.;Abdulrahman, Basant A.;Amer, Amal O.
通讯作者：
Amer, Amal O.
影响因子：
5.3
作者：
Bruscia EM;Bonfield TL
通讯作者：
Bonfield TL
DOI：
10.1073/pnas.1000041107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Helaine, Sophie;Thompson, Jessica A.;Holden, David W.
通讯作者：
Holden, David W.
影响因子：
5.5
作者：
Kotrange, Sheetal;Kopp, Benjamin;Amer, Amal O.
通讯作者：
Amer, Amal O.
影响因子：
13.3
作者：
Luciani, Alessandro;Villella, Valeria Rachela;Maiuri, Luigi
通讯作者：
Maiuri, Luigi