Mycobacterium tuberculosis ESAT6 modulates host innate immunity by downregulating miR-222-3p target PTEN

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2022-01, Vol.1868 (1), p.166292-166292, Article 166292
• Main Authors: Zonghai, Chen, Tao, Luo, Pengjiao, Ma, Liang, Ge, Rongchuan, Zhao, Xinyan, Wang, Wenyi, Ni, Wei, Liao, Yi, Wang, Lang, Bao
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - genetics; Bacterial Proteins - genetics; Disease Models, Animal; ESAT6; Host-Pathogen Interactions - genetics; Humans; Immunity, Innate - genetics; Innate Immunnity; Mice; MicroRNAs - genetics; MiR-222-3p; Mycobacterium smegmatis - genetics; Mycobacterium smegmatis - pathogenicity; Mycobacterium Tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - pathogenicity; PTEN; PTEN Phosphohydrolase - genetics; Tuberculosis - genetics; Tuberculosis - immunology; Tuberculosis - pathology; VO-Ohpic trihydrate
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2021.166292

Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, and it is instant to discover novel anti-TB drugs due to the rapidly growing drug-resistance TB. Mycobacterium tuberculosis (Mtb) secreted effector ESAT6 plays a critical role in modulation miRNAs to regulate host defense mechanisms during Mtb infection, it can be a possible target for new tuberculosis drugs. The non-tuberculous mycobacteria Mycobacterium smegmatis (M. smegmatis) and Mtb have high gene homology but no pathogenicity. We used ESAT6 to interfere with macrophages or mice infected by M. smegmatis and determined that it enhanced the survival rate of bacteria and regulated miR-222-3p target PTEN. Expression of miR-222-3p reduced and PTEN enhanced with the progression of macrophages infected by M. smegmatis with ESAT6 co-incubation. MiR-222-3p overexpression diminished M. smegmatis survival and upregulated proinflammatory cytokines. VO-Ohpic trihydrate (PTEN inhibitor) reduced M. smegmatis survival and upregulated proinflammatory cytokines in vivo and in vitro, and VO-Ohpic trihydrate reversed the tissue damage of mouse organs caused by ESAT6. These results uncover an ESAT6 dependent role for miR-222-3p and its target PTEN in regulating host immune responses to bacterial infection and may provide a potential site for the development of anti-tuberculosis drugs that specifically antagonize the virulence of ESAT6. •ESAT6 downregulates miR-222-3p in M. smegmatis-infection.•PTEN is a target of miR-222-3p.•PTEN is regulated by ESAT6.•PTEN regulates host innate immunity through ESAT6/miR-222-3p/PTEN axis.•VO-Ohpic trihydrate (PTEN inhibitor) antagonizes the virulence of ESAT6.