Abstract

Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world’s leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection.

Highlights

  • Tuberculosis (TB) is one of the top 10 causes of death and the leading cause from a single infectious agent, exceeding both malaria and HIV

  • To investigate the function of FasR in M. tuberculosis, and considering that fasR is essential for M. smegmatis viability, we first constructed an M. tuberculosis conditional knockdown strain in fasR (Figure 1A)

  • We have shown that the absence of FasR and, reduced levels of fas-acpS have a strong impact on the composition of the M. tuberculosis cell envelope, and on bacterial multiplication within macrophages

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Summary

Introduction

Tuberculosis (TB) is one of the top 10 causes of death and the leading cause from a single infectious agent, exceeding both malaria and HIV. The composition and complexity of the cell envelope is the most distinctive feature of Mycobacterium tuberculosis, the etiologic agent of human TB. Biochemical and microscopic data revealed that the mycobacterial envelope consists of three discrete entities: a plasma membrane surrounded by a complex cell wall and an outermost layer called the capsule in pathogenic species (Chiaradia et al, 2017; Daffé and Marrakchi, 2019). The M. tuberculosis cell wall consists of peptidoglycan covalently linked to arabinogalactan esterified by mycolic acids (MA), which form the inner leaflet of the outer membrane bilayer (mycomembrane). The outer leaflet of this membrane is composed of free, non-covalently bound lipids and glycolipids like trehalose monomycolates (TMM), trehalose dimycolates (TDM), glycerol monomycolates, glucose monomycolates, phthiocerol dimycocerosates (PDIM), poly acylated trehaloses (PAT), sulfolipids (SL), phosphatidylinositol mannosides (PIM), phenolic glycolipids (PGL), and mannose-capped lipoarabinomannans (Man-Lam; Brennan and Nikaido, 1995; Daffe and Reyrat, 2008)

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