Mycobacterium tuberculosis (Mtb) is a deadly pathogen and a causative agent of tuberculosis. It is estimated that these infectious bacteria lead to 1.3 million deaths globally. The Mtb infects lungs and leads to prolonged illness, producing cough, progressive fatigue and cachexia with loss of muscle mass, pleuritic chest pain, and hemoptysis, eventually leading to lung damage. In addition to lung damage, TB is accompanied by systemic disturbances like an altered immune-metabolic axis, including changes in insulin resistance, vitamin D signaling, iron metabolism, etc.
The involvement of the liver in systemic tuberculosis has been a less explored area. It is the primary hub where most of the drugs undergo enzymatic modifications. Further, the liver is highly tolerant when it comes to averting organ damage in case of pathogenic infections. The spread of Mtb to this important metabolic organ and the biological changes it induces are of clinical significance. In a recent study published in the eLIFE journal, researchers have established evidence that Mtb creates a favourable environment in the form of lipid droplets, enriching the transcription factor ‘PPARγ’ and scavenging lipids from the host cells, overall making the environment replication-friendly for the bacteria. The study identified the presence of Mtb within hepatocytes in a murine aerosol infection model after the fourth week.
The researchers demonstrated the active involvement of the liver in a murine model, which was infected with TB through aerosol infection. They show that Mtb perturbs the hepatocytes (primary liver cells), which becomes a busy hub for bacterial replication. Infection of Mtb in the hepatocytes leads to extensive biological changes in liver cells, remodeling intracellular growth, localization, drug sensitivity and further increased fatty acid biogenesis and TAG biosynthesis. The study provides key fundamental insights with respect to the intracellular growth, localization, drug sensitivity and metabolic adaptation of Mtb within hepatocytes.
There is a growing body of evidence that suggests that Mtb can survive in the cells and acquire resistance to antibiotics. Since the liver is the major site for drug metabolism, the scientists analyzed the influence of Mtb in liver cells and its effects on commonly used anti-TB drugs. The data from the study showed that Mtb infection of hepatocytes induces host drug-metabolizing enzymes that may result in either decreased bioavailability or increased inactivation of the anti-TB drugs. In doing so, the bacteria shield themselves against the common anti-TB drugs.
The researchers, through this study, propose that infection of hepatocytes by Mtb during the chronic phase can contribute to significant changes in disease progression, TB treatment, and development of infection-induced metabolic diseases.
Overall, the study identifies hepatocytes as a site for Mtb survival and replication. Mtb infection disrupts lipid metabolism in the liver cells via PPARγ transcription factor, leading to increased levels of fatty acids and triglycerides, which are utilized by the bacteria for their growth. These findings underscore hepatocytes as a novel niche for Mtb persistence, shedding light on the pathogenesis of TB.
This was a collaborative study between researchers based at the BRIC-NII, ICGEB New Delhi, CSIR-IMTECH Chandigarh, CSIR-IGIB and IISER Pune.
Reference:
Sarkar Binayak, Singh Jyotsna, Yadav Mohit, Sharma Priya, Sharma Raman Deep, Singh Shweta, Chandramouli Aakash, Mehdiratta Kritee, Kumar Ashwani, Kamat Siddhesh S, Ghorpade Devram S, Mohanty Debasisa, Kumar Dhiraj, Gokhale Rajesh S (2025) PPARγ mediated enhanced lipid biogenesis fuels Mycobacterium tuberculosis growth in a drug-tolerant hepatocyte environment eLife 14:RP103817 https://doi.org/10.7554/eLife.103817.1
Written by Gargi Deshmukh