Role of TNF in the altered interaction of dormant Mycobacterium tuberculosis with host macrophages.
Role of TNF in the altered interaction of dormant Mycobacterium tuberculosis with host macrophages.
复制标题
DOI：
10.1371/journal.pone.0095220
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kaushal D
中科院分区：
文献类型：
--
作者：
Gautam US;Mehra S;Ahsan MH;Alvarez X;Niu T;Kaushal D
结核分枝杆菌(Mtb)持续存在于肺肉芽肿内，尽管受到包括缺氧在内的各种应激条件的影响。我们假设宿主吞噬细胞对结核分枝杆菌缺氧的反应发生了根本性的改变，并设计了体外实验来研究这一现象。用低氧应激(Mtb-H)和好氧培养的Mtb(Mtb-A)感染恒河猴骨髓来源的巨噬细胞(Rh-BMDM)，比较宿主对Mtb感染的反应。通过使用RNAi获得了机械学上的见解。在Rh-BMDM中，MTB-H在生长过程中积累了显著较低的细菌负荷，同时产生了截然不同的宿主转录谱(两组中只有2%的基因被感染所干扰)。这一特征的一个关键成分是Mtb-H-相比感染Mtb-A的Rh-BMDM显著更高的肿瘤坏死因子和细胞凋亡率。RNAi沉默肿瘤坏死因子逆转了对结核分枝杆菌复制的显著控制。这些结果表明，吞噬细胞快速清除缺氧条件下的细菌可能是一种机制。总之，与常氧培养的结核分枝杆菌相比，缺氧条件下的结核分枝杆菌与宿主巨噬细胞发生了显著不同的相互作用。这些相互作用导致了肿瘤坏死因子信号通路的诱导、细胞凋亡的激活和DNA损伤应激反应。我们的结果表明，Mtb-H杆菌对肿瘤坏死因子支配的杀伤力特别敏感。
Mycobacterium tuberculosis (Mtb) persists within lung granulomas, despite being subjected to diverse stress conditions, including hypoxia. We hypothesized that the response of host phagocytes to Mtb experiencing hypoxia is radically altered and designed in vitro experiment to study this phenomenon. Hypoxia-stressed (Mtb-H) and aerobically grown Mtb (Mtb-A) were used to infect Rhesus Macaque Bone Marrow Derived Macrophages (Rh-BMDMs) and the comparative host response to Mtb infection studied. Mechanistic insights were gained by employing RNAi. Mtb-H accumulated significantly lower bacterial burden during growth in Rh-BMDMs, concomitantly generating a drastically different host transcriptional profile (with only <2% of all genes perturbed by either infection being shared between the two groups). A key component of this signature was significantly higher TNF and apopotosis in Mtb-H- compared to Mtb-A-infected Rh-BMDMs. Silencing of TNF by RNAi reversed the significant control of Mtb replication. These results indicate a potential mechanism for the rapid clearance of hypoxia-conditioned bacilli by phagocytes. In conclusion, hypoxia-conditioned Mtb undergo significantly different interactions with host macrophages compared to Mtb grown in normoxia. These interactions result in the induction of the TNF signaling pathway, activation of apoptosis, and DNA-damage stress response. Our results show that Mtb-H bacilli are particularly susceptible to killing governed by TNF.
登录
查看更多内容
影响因子：
6.4
作者：
Mehra, Smriti;Golden, Nadia A.;Kaushal, Deepak
通讯作者：
Kaushal, Deepak
影响因子：
4.4
作者：
Chen, Minjian;Gan, Huixian;Remold, Heinz G.
通讯作者：
Remold, Heinz G.
影响因子：
4.8
作者：
Roberts, DM;Liao, RLP;Sherman, DR
通讯作者：
Sherman, DR
影响因子：
3.1
作者：
KHELEF, N;ZYCHLINSKY, A;GUISO, N
通讯作者：
GUISO, N
影响因子：
4.4
作者：
Mariotti, Sabrina;Pardini, Manuela;Nisini, Roberto
通讯作者：
Nisini, Roberto