Brucella spp., the causative agents of brucellosis, are facultative intracellular pathogens lacking classical virulence factors, and the disease represents one of the most prevalent zoonoses worldwide. Nevertheless, Brucella efficiently modulates the expression of genes associated with host cellular metabolism and immune evasion. The SIRT1 protein is a member of the NAD + ‐dependent class III histone deacetylase family that regulates apoptosis, autophagy, and inflammatory responses during cellular stress. In this study, we demonstrate that B. abortus infection of macrophage cells downregulates the expression of SIRT1 . SIRT1 negatively regulated B. abortus intracellular proliferation. Infection reduced NAD + levels in macrophages, but stimulation of SIRT1 expression with resveratrol attenuated this inhibitory effect. SIRT1 negatively regulated B. abortus ‐induced acetylation modification of the FOXO1 transcription factor. Furthermore, B. abortus infection promoted the increase of the LC3‐II and p62 autophagy markers in macrophages while inhibiting expression of the Atg7 marker. Conversely, resveratrol treatment decreased B. abortus ‐induced LC3‐II and p62 expression and promoted Atg7 expression, whereas knockdown of SIRT1 exerted the opposing effects. In addition, B. abortus infection impaired lysosomal function by inhibiting key proteins m‐CTSB and m‐CTSD, reducing phagosome‐lysosome fusion, and promoting phagosome accumulation. Resveratrol‐mediated SIRT1 activation alleviated B. abortus ‐induced inhibition of m‐CTSB and m‐CTSD expression. In conclusion, our findings reveal that B. abortus modulates intracellular proliferation and macrophage lysosomal function through SIRT1, which leads to autophagic modulation, thereby providing a novel therapeutic target for treatment of brucellosis.
Yang et al. (Thu,) studied this question.