Crosstalk Between Staphylococcus aureus and Innate Immunity: Focus on Immunometabolism

Abstract

Staphylococcus aureus is a leading cause of bacterial infections globally in both healthcare and community settings. The success of this bacterium is the product of an expansive repertoire of virulence factors in combination with acquired antibiotic resistance and propensity for biofilm formation. S. aureus leverages these factors to adapt to and subvert the host immune response. With the burgeoning field of immunometabolism, it has become clear that the metabolic program of leukocytes dictates their inflammatory status and overall effectiveness in clearing an infection. The metabolic flexibility of S. aureus offers an inherent means by which the pathogen could manipulate the infection milieu to promote its survival. The exact metabolic pathways that S. aureus influences in leukocytes are not entirely understood, and more work is needed to understand how S. aureus co-opts leukocyte metabolism to gain an advantage. In this review, we discuss the current knowledge concerning how metabolic biases dictate the pro- vs. anti-inflammatory attributes of various innate immune populations, how S. aureus metabolism influences leukocyte activation, and compare this with other bacterial pathogens. A better understanding of the metabolic crosstalk between S. aureus and leukocytes may unveil novel therapeutic strategies to combat these devastating infections.

Keywords: Staphylococcus aureus; biofilm; immunometabolism; lactate; macrophage; myeloid-derived suppressor cell.

Figure 1

Metabolic shifts in leukocytes define resting from inflammatory states. Immune cells normally respire under resting conditions to provide sufficient energy (ATP) for survival. Upon activation, although energy production is somewhat increased, a significant portion of the metabolic flow is dedicated to producing metabolic intermediates (Effector Metabolites) that are used to generate inflammatory mediators (i.e. cytokines, inflammatory lipids, etc.) to promote leukocyte effector functions (Immune Response). S. aureus, either through competition for metabolic resources or by releasing immunomodulatory metabolites, can interfere with this process to disrupt a productive immune response. Monocyte (MO), macrophage (Mφ), neutrophil (PMN), and granulocytic myeloid-derived suppressor cell (G-MDSC). Figure created with BioRender.

Figure 2

Macrophage metabolic remodeling during an immune response. Following Toll-like receptor (TLR) activation, macrophages undergo metabolic rewiring to promote inflammatory mediator production. The TCA cycle breaks at two points, isocitrate dehydrogenase (IDH) that causes the accumulation of aconitate, which is converted by immune responsive gene 1 (IRG1) to form itaconate, and succinate dehydrogenase (SDH) that leads to succinate accumulation. While this process normally augments proinflammatory activity, excess itaconate production eventually causes a shift to promote the expression of anti-inflammatory genes. Figure created with BioRender.

Figure 3

S. aureus biofilm regulates leukocyte inflammatory activity. S. aureus biofilms employ a number of strategies to create an infection milieu to ensure persistence. Two of these approaches involve the action of either bacterial-derived metabolites or intrinsic reprogramming of monocyte/macrophage metabolism that culminate in the expression of anti-inflammatory genes. (Top) Biofilm augments oxidative metabolism in infiltrating monocytes and macrophages that biases them towards an anti-inflammatory phenotype. (Bottom) In MDSCs and macrophages, biofilm-derived lactate causes epigenomic remodeling that leads to an increase in IL-10 expression. Figure created with BioRender.

Figure 4

S. aureus small colony variants (SCVs) interfere with the establishment of trained immunity. The generation of SCVs with mutations in metabolic pathways exert influence over the formation of trained immunity. S. aureus SCVs with hyperactive fumarate hydratase (fumC) quickly degrade mitochondrial pools of fumarate, which leads to an upregulation of glycolysis and impaired formation of trained immunity. The absence of fumuarate causes KDM5 to become active, which removes the methylation marks around the promoters of pro-inflammatory genes, thereby decreasing the accessilibity of the chromatin in these regions. Figure created with BioRender.