Utilization of Host Polyamines in Alternatively Activated Macrophages Promotes Chronic Infection by Brucella abortus

Abstract

Treatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple drugs. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs); however, knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAMs is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by interleukin 4 (IL-4)/IL-13 treatment. Production of polyamines by infected AAMs promoted both intracellular survival of B. abortus and chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of the putative putrescine transporter encoded by potIHGF reduced both intracellular survival in AAMs and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAMs promotes chronic persistence of B. abortus within this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.

Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization

“…The altered metabolic state of M2 macrophages might also support the persistence of intracellular pathogens, which in the case of Salmonella appears dependent on the host transcription factor PPARd (Eisele et al, 2013;Xavier et al, 2013). Indeed, several other pathogens, including Mycobacterium tuberculosis (Huang et al, 2018;Sahu et al, 2017), Coxiella (Benoit et al, 2008), Francisella (Shirey et al, 2008), and Brucella (Kerrinnes et al, 2018), drive an anti-inflammatory M2-like host response. Whereas GRA18 from Toxoplasma gondii interacts with GSK3 and promotes transcription of anti-inflammatory genes, the mechanism is likely to be different because GRA18 functions in a b-catenin-dependent fashion (He et al, 2018).…”

Salmonella-Driven Polarization of Granuloma Macrophages Antagonizes TNF-Mediated Pathogen Restriction during Persistent Infection

“…During intracellular bacterial infections, infected macrophages typically exhibit a classically activated (M1-like) phenotype and restrict the pathogen through mechanisms such as pyroptosis and production of pro-inflammatory cytokines, including tumor necrosis factor (TNF) (Storek and Monack, 2015). Emerging evidence suggests an alternatively activated (M2like) phenotype is associated with intracellular bacterial growth and persistence (Eisele et al, 2013;Huang et al, 2018;Kerrinnes et al, 2018;Sahu et al, 2017;Stapels et al, 2018). Computational modeling studies have shown that the ratio of M1 versus M2 activities within Mycobacterium tuberculosis (Mtb) granulomas can predict controlled infection or disseminated disease (Marino et al, 2015).…”

Cytokine-Mediated Regulation of ARG1 in Macrophages and Its Impact on the Control of Salmonella enterica Serovar Typhimurium Infection

“…The different L-arginine catabolizing pathways have been shown to be of central importance for host resistance to infection with intracellular microbes, mainly by generating the formation of NO to enforce anti-microbial host responses, but also via the synthesis of polyamines, resulting in a pathogen-friendly nutritional environment [ 9 , 44 , 45 , 46 ]. A central enzyme controlling L-arginine levels in infected macrophages is ARG1, which cleaves L-arginine into ornithine and urea and thereby limits the availability of L-arginine for NO formation.…”