Host Lipid and Mitochondrial Metabolism Networks as Functional Targets for Novel Antimicrobials against Intracellular Bacteria

Introduction/Rationale:: Host lipid metabolism has been implicated in viral and bacterial pathogenesis. Here we identify that temporal manipulation of host cell lipid synthesis pathways via the targeting of a master regulator of lipid biogenesis by unique lipids present in the virulent intracellular bacterium Francisella tularensis (FT) is a critical element of this bacterium’s virulence.

Methods: We utilized both in vitro and in vivo models to establish the pathways associated with Franicsella lipid (FTL) modulation of host cell function.

Results: Pretreatment of cells with FTL triggered lipid droplet formation and significantly increased replication of FT. We observed that FTL and FT triggered rapid and transient upregulation of genes associated with lipid biogenesis. Specifically, increased expression of the master regulator PGC-1a, ACOX-1, and FASN was observed within the first 8 hours of exposure to FTL or FT infection. PGC-1a controls lipid droplet biogenesis and mitochondrial function, both of which are critical for optimal replication of FT. Inhibition of PGC-1a dramatically impaired formation of lipid droplets in untreated and FTL treated cells. Importantly, impairment of PGC1-a also completely controlled FT replication in a fashion that was independent of the generation of reactive oxygen species.

Conclusion: Our data identify the unique lipids associated with FT play an important role in pathogenesis via their ability to control multiple metabolic nodes within the host cell. Specifically, their ability to rapidly activate host molecules that drive lipid droplet biogenesis and mitochondrial function greatly improved FT replication and spread. Our data also show that targeting of these pathways, e.g. inhibiting PGC-1a, with drugs that are well tolerated in other models of inflammation may be an effective alternative to or supplemental treatment for antibiotic intervention.