Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice
Jennifer A. Philips, MD, PhD, Theodore and Bertha Bryan Professor, Departments of Medicine and Molecular Microbiology; Co-director, Infectious Diseases Division, recently co-authored a Nature Microbiology publication, with Ekansh Mittal, PhD, Instructor of Medicine, WashU Division of Infectious Diseases, on Mycobacterium tuberculosis (Mtb).
Dr. Philips is the principal investigator of an NIH-funded lab that studies how Mycobacterium tuberculosis evades the host immune response. M. tuberculosis causes TB, one of the world’s most deadly infections. It has infected humans for millennia and is highly adapted to navigate the complexities of the human immune system. The discoveries in the Philips laboratory have delineated how Mtb blocks lysosomal trafficking, alters host metabolism and impairs antigen presentation. Her laboratory has identified clinically available drugs that restore the ability of the host to clear M. tuberculosis, overcoming key immune evasion strategies of Mtb. These findings may lead to novel host-directed therapies for TB.
Insight on the Nature Microbiology Publication
Mycobacterium tuberculosis (Mtb) continues to be a global health challenge, killing more people yearly than any other infectious pathogen. An effective tuberculosis (TB) vaccine remains out of reach due to our incomplete understanding of the mechanisms of host immunity to Mtb and how they are countered by Mtb. This study represents a significant conceptual breakthrough in TB research by demonstrating that the Mtb virulence lipid phthiocerol dimycocerosate (PDIM) impairs autophagy-mediated clearance of Mtb in vivo.
PDIM is a lipid found in the outer envelope of Mtb. Over twenty years ago, landmark studies identified PDIM as important for Mtb virulence in mice. When Mtb are grown in the laboratory, because it takes a lot of energy to make PDIM, the bacteria often lose the ability to make PDIM in order to grow faster. However, Mtb bacilli isolated from people have the ability to make PDIM, highlighting the importance of PDIM in causing disease in human populations. However, the mechanism by which PDIM promotes virulence in vivo was not understood.
Our study makes an important contribution by demonstrating how a critical Mtb virulence factor promotes the ability of the bacteria to disseminate in macrophages in the lungs. This study enhances our understanding of how Mtb evades immunity, which may enable better therapies and an effective vaccine for TB.
Jennifer A. Philips, MD
Mtb is transmitted by aerosol, and it first infects alveolar macrophages (AMs) in the airways of the lung. Over time, Mtb disseminates from AMs to a variety of different myeloid populations that are recruited to the site of infection. However, instead of leading to bacterial clearance, Mtb survives and grows in these cells. We found that while PDIM is dispensable for Mtb to infect and grow in AMs, PDIM is required for the bacilli to overcome autophagy and effectively infect other macrophage populations. Thus, these findings defined, for the first time, the role of PDIM during Mtb infection.
They also explains why autophagy pathways are not effective in controlling Mtb, showing that PDIM impairs this host defense pathways. Previous work suggested that autophagy in macrophages promotes bacterial degradation and modulates the inflammatory response. Unexpectedly we found that during chronic TB infection, autophagy in myeloid cells is also required for B cell follicle formation, demonstrating an unrecognized function of autophagy in the context of chronic TB infection.
Mittal, E., Prasad, G.V.R.K., Upadhyay, S. et al. Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice. Nat Microbiol (2024). https://doi.org/10.1038/s41564-024-01797-5