Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity.
Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity.
复制标题
缺氧条件下分枝杆菌阻断宿主脂肪酸代谢以抑制抗结核免疫
DOI：
10.1038/s41421-021-00301-1
复制
发表时间：
2021-10-05
期刊：
影响因子：
33.5
通讯作者：
Ge B
中科院分区：
文献类型：
--
作者：
Yang H;Wang F;Guo X;Liu F;Liu Z;Wu X;Zhao M;Ma M;Liu H;Qin L;Wang L;Tang T;Sha W;Wang Y;Chen J;Huang X;Wang J;Peng C;Zheng R;Tang F;Zhang L;Wu C;Oehlers SH;Song Z;She J;Feng H;Xie X;Ge B
病原性分枝杆菌在潜伏性结核（TB）感染期间诱导形成缺氧性肉芽肿，其中免疫系统包含但不能消除分枝杆菌。脂肪酸代谢相关基因在分枝杆菌基因组中相对过多，分枝杆菌喜欢宿主来源的脂肪酸作为营养源。然而，分枝杆菌是否以及如何调节宿主脂肪酸代谢以驱动肉芽肿进展仍然未知。在这里，我们报告说，分枝杆菌在缺氧下显着分泌蛋白Rv 0859/MMAR_4677（脂肪酸降解A，FadA），这也是丰富的结核性肉芽肿。FadA充当将宿主乙酰辅酶A转化为乙酰乙酰辅酶A的乙酰转移酶。降低的乙酰辅酶A水平抑制H3 K9 Ac介导的宿主促炎细胞因子II 6的表达，从而促进肉芽肿进展。此外，补充乙酸盐增加乙酰辅酶A的水平并抑制肉芽肿的形成。我们的研究结果表明缺氧诱导的分枝杆菌蛋白通过调节宿主脂肪酸代谢来抑制宿主免疫的一种意想不到的机制，并提出了一种新的结核感染治疗策略的可能性。
Pathogenic mycobacteria induce the formation of hypoxic granulomas during latent tuberculosis (TB) infection, in which the immune system contains, but fails to eliminate the mycobacteria. Fatty acid metabolism-related genes are relatively overrepresented in the mycobacterial genome and mycobacteria favor host-derived fatty acids as nutrient sources. However, whether and how mycobacteria modulate host fatty acid metabolism to drive granuloma progression remains unknown. Here, we report that mycobacteria under hypoxia markedly secrete the protein Rv0859/MMAR_4677 (Fatty-acid degradation A, FadA), which is also enriched in tuberculous granulomas. FadA acts as an acetyltransferase that converts host acetyl-CoA to acetoacetyl-CoA. The reduced acetyl-CoA level suppresses H3K9Ac-mediated expression of the host proinflammatory cytokine Il6, thus promoting granuloma progression. Moreover, supplementation of acetate increases the level of acetyl-CoA and inhibits the formation of granulomas. Our findings suggest an unexpected mechanism of a hypoxia-induced mycobacterial protein suppressing host immunity via modulation of host fatty acid metabolism and raise the possibility of a novel therapeutic strategy for TB infection.
登录
查看更多内容
DOI：
10.1038/s41579-018-0013-4
发表时间：
2018-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Ehrt S;Schnappinger D;Rhee KY
通讯作者：
Rhee KY
影响因子：
8.7
作者：
Matty MA;Roca FJ;Cronan MR;Tobin DM
通讯作者：
Tobin DM
影响因子：
3.1
作者：
Nandy A;Mondal AK;Pandey R;Arumugam P;Dawa S;Jaisinghani N;Rao V;Dash D;Gandotra S
通讯作者：
Gandotra S
影响因子：
3.1
作者：
Ladel, CH;Blum, C;Kaufmann, SHE
通讯作者：
Kaufmann, SHE
影响因子：
64.8
作者：
Baell, Jonathan B.;Leaver, David J.;Thomas, Tim
通讯作者：
Thomas, Tim