Interception of host fatty acid metabolism by mycobacteria under hypoxia to suppress anti-TB immunity

Author:

Yang Hua,Wang Fei,Guo Xinya,Liu Feng,Liu Zhonghua,Wu Xiangyang,Zhao Mengmeng,Ma Mingtong,Liu Haipeng,Qin Lianhua,Wang Lin,Tang Tianqi,Sha Wei,Wang Yang,Chen Jianxia,Huang Xiaochen,Wang Jie,Peng Cheng,Zheng Ruijuan,Tang Fen,Zhang Lu,Wu Chunyan,Oehlers Stefan H.ORCID,Song Zhigang,She Jialei,Feng Hua,Xie Xunwei,Ge BaoxueORCID

Abstract

AbstractPathogenic 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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Genetics,Molecular Biology,Biochemistry

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