Sphingolipids: A double-edged sword in the defense against Mycobacterium tuberculosis.

Abstract

Abstract Mycobacterium tuberculosis (Mtb) is a pathogen with a massive global health impact, and yet fundamental questions remain regarding the underlying mechanisms of its entry and subversion of innate immune mechanisms – particularly the manners in which host lipids influence the course of an infection. This pathogen gains entry to host alveolar macrophages via phagocytosis and, within the phagosome, Mtb perturbs host lipid metabolism and distribution. Here, we've shown that Mtb relies on an intact sphingolipid biosynthesis pathway to gain entry to host cells but that sphingolipids restrict the intracellular growth of this pathogen. We used genetic ablation and small molecule inhibition to perturb sphingolipid biosynthesis, resulting in reduced Mtb uptake across multiple phagocytic cell types without affecting receptor mediated endocytosis. Mechanistically, we visualized the dynamics of several signaling events during phagocytosis to demonstrate that sphingolipid deficiency results in poor initiation of phagocytic signaling. Intriguingly, sphingolipid inhibition at later stages of infection may result in enhanced intracellular Mtb growth and accelerated lysosomal damage and subsequent phagolysosomal escape. This study has revealed that the sphingolipid family may constitute a double-edged sword which plays multiple roles during Mtb infection. In understanding the interplay between Mycobacterium tuberculosis and host factors such as sphingolipids, we hope to identify novel methods of treatment for this ancient and global pathogen. Supported by grants from NIH (R21 3R21AI124225-01A1 and R01 1R01AI14154 9-01A1)