PPARγ mediated enhanced lipid biogenesis fuels Mycobacterium tuberculosis growth in a drug-tolerant hepatocyte environment

• DOI: 10.7554/elife.103817.1
• Publication Date: 2025-01-06T17:26:00Z
• Authors: Binayak Sarkar; Jyotsna Singh; Mohit Yadav; Priya Sharma; Raman Deep Sharma; Shweta Singh; Aakash Chandramouli; Kritee Mehdiratta; Ashwani Kumar; Siddhesh S Kamat; Devram S Ghorpade; Debasisa Mohanty; Dhiraj Kumar; Rajesh S Gokhale

Mycobacterium tuberculosis (Mtb) infection of the lungs, besides producing prolonged cough with mucus, also causes progressive fatigue and cachexia with debilitating loss of muscle mass. While anti-tuberculosis (TB) drug therapy is directed toward eliminating bacilli, the treatment regimen ignores the systemic pathogenic derailments that probably dictate TB-associated mortality and morbidity. Presently, it is not understood whether Mtb spreads to metabolic organs and brings about these impairments. Here we show that Mtb creates a replication-conducive milieu of lipid droplets in hepatocytes by upregulating transcription factor PPARγ and scavenging lipids from the host cells. In hepatocytes, Mtb shields itself against the common anti-TB drugs by inducing drug-metabolizing enzymes. Infection of the hepatocytes in the in vivo aerosol mice model can be consistently observed post-week 4 along with enhanced expression of PPARγ and drug-metabolizing enzymes. Moreover, histopathological analysis indeed shows the presence of Mtb in hepatocytes along with granuloma-like structures in human biopsied liver sections. Hepatotropism of Mtb during the chronic infectious cycle results in immuno-metabolic dysregulation that could magnify local and systemic pathogenicity, altering clinical presentations.