Abstract
With a disease as widespread and destructive as tuberculosis, more effective drugs and healthcare strategies, in addition to the current antibiotics regimen, are crucial for the enhanced well-being of millions of people suffering from the disease. Host-directed therapy is a new and emerging concept in treating chronic infectious diseases, such as tuberculosis. Repurposing of anti-cancer drugs, such as everolimus, may be an effective way to supplement the standard antibiotic treatment. Individuals with type 2 diabetes are increasingly susceptible to co-morbidities and co-infections including Mycobacterium tuberculosis, the causative agent of tuberculosis. We demonstrated in this study that in vitro everolimus treatment of granulomas from individuals with type 2 diabetes caused significant reduction in the viability of Mycobacterium tuberculosis.Further investigations revealed the effects of everolimus in targeting foamy macrophages, a macrophage phenotype that forms around granulomas, and is characterized by a higher lipid accumulation inside the cells. These foamy macrophages are thought to harbor dormant bacilli, which are potential sources of disease reactivation. Therefore, blocking foamy macrophage formation would help better killing of intracellular bacteria. Here, we report the potential of everolimus treatment to downregulate lipid content within the foamy macrophages of in vitro granulomas, thus leading to a potential decrease in the number of foamy macrophages and a more robust response to Mycobacterium tuberculosis.
Highlights
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tb), is estimated to infect nearly 10 million people a year [1]
We first tested the ability of everolimus in inhibiting the growth of intracellular M. tb within in vitro granulomas generated with peripheral blood mononuclear cells (PBMCs) from individuals with type 2 diabetes mellitus (T2DM)
There was a significant decrease in bacterial colony-forming units (CFUs) at both 8 days and 15 days post-infection in granulomas treated with 1 nM everolimus, compared to untreated control groups
Summary
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tb), is estimated to infect nearly 10 million people a year [1]. M. tb is transmitted through inhalation of aerosolized droplets, which first infects the alveoli in the lungs and spreads throughout the body, infecting other organs. Macrophages ingest and destroy the M. tb pathogen. While some of the infection may be cleared with bacterial killing, the macrophages begin to aggregate around the infected cell and create a granuloma, which acts to enclose and suppress the infection instead of clearing it, leading to latent tuberculosis (LTBI). The infection remains latent in about 1.7 billion people around the world [1]. The granuloma suppresses M. tb replication by creating a hypoxic environment, depriving the pathogen
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call