FasR regulates fatty acid biosynthesis and is essential for virulence of Mycobacterium tuberculosis
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2020-10-27
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Frontiers Media
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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.
Palabras clave
Tuberculosis, Fatty Acid Biosynthesis, Lipid Homeostasis, Mycobacteria, Virulence, Mycobacterial Cell Envelope