Background:Staphylococcus aureus (S. aureus) is a common cause of hospital- and community-acquired infections that can result in various clinical manifestations ranging from mild to severe disease. The bacterium utilizes different combinations of virulence factors and biofilm formation to establish a successful infection, and the emergence of methicillin- and vancomycin-resistant strains introduces additional challenges for infection management and treatment. Summary: Metabolic programming of immune cells regulates the balance of energy requirements for activation and dictates pro- versus anti-inflammatory function. Recent investigations into metabolic adaptations of leukocytes and S. aureus during infection indicate that metabolic crosstalk plays a crucial role in pathogenesis. Furthermore, S. aureus can modify its metabolic profile to fit an array of niches for commensal or invasive growth. Key Messages: Here we focus on the current understanding of immunometabolism during S. aureus infection and explore how metabolic crosstalk between the host and S. aureus influences disease outcome. We also discuss how key metabolic pathways influence leukocyte responses to other bacterial pathogens when information for S. aureus is not available. A better understanding of how S. aureus and leukocytes adapt their metabolic profiles in distinct tissue niches may reveal novel therapeutic targets to prevent or control invasive infections.

Staphylococcus aureus (S. aureus) is a common human commensal and significant opportunistic pathogen. Approximately 30% of humans are carriers of S. aureus, primarily in the nose and frequently at other body sites such as the skin and throat [1, 2], and S. aureus colonization is a known risk factor for developing invasive infections [3]. S. aureus is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, pneumonia, osteomyelitis, and medical device infections typified by biofilm formation. Disease typically originates from the invasion of colonizing strains into the bloodstream or following a breach of protective epithelial or mucosal barriers during injury or medical device placement; however, in rare cases, isolates can be transferred between individuals. S. aureus encodes an array of virulence factors and immune evasion strategies that facilitate both commensal and opportunistic lifestyles [4‒6].

S. aureus can cause either acute or chronic infections, which is dictated by various host and bacterial factors [7‒10]. In terms of leukocyte responses, neutrophils (PMNs) play a significant role in controlling infection as patients with chronic granulomatous disease, typified by mutations in nicotinamide dinucleotide phosphate (NADPH) oxidase, are more susceptible to recurrent S. aureus infections due to impaired reactive oxygen species (ROS) production [11]. Macrophages (MΦs), T cells, and B cells also play important roles in regulating bacterial growth. However, S. aureus has the potential to circumvent these protective responses by a number of mechanisms [12], including inhibiting PMN and MΦ extravasation, activation, and phagocytosis [13‒15]. S. aureus also encodes various toxins such as leukocidins, phenol-soluble modulins, and hemolysins that kill leukocytes and promote bacterial survival [16‒18]. Furthermore, S. aureus can form biofilm, which programs the immune response to an anti-inflammatory state that facilitates chronic infection [19‒23].

Current attempts to develop a S. aureus vaccine have proven unsuccessful, highlighting the immune evasive properties of the pathogen [24, 25]. The poor translation of protection from animal models to humans is likely influenced by S. aureus virulence factors that selectively target human but not mouse leukocytes, human-adapted S. aureus strains, and differences in immune reactivity between species [26‒28]. Individuals with S. aureus-reactive antibodies can become infected with the pathogen and S. aureus causes recurrent infections [29‒31], additional evidence that the organism possesses a heightened ability to evade immune mechanisms, unlike other bacteria where effective vaccines have been developed. Newer vaccine platforms being explored in mouse models are targeting different S. aureus antigens (i.e., α-toxin, leukocidins) than those used in prior clinical trials [32, 33], but it remains to be determined whether this will translate into clinical efficacy. S. aureus also has a high propensity to acquire antibiotic resistance through horizontal gene transfer as reflected by the increased prevalence of methicillin-resistant and vancomycin-resistant S. aureus strains, representing another major challenge for treatment [34, 35]. In addition, S. aureus exhibits antibiotic tolerance during biofilm infections such as endocarditis, medical device-associated infections, and conjunctivitis, representing an additional barrier to treatment [36].

Therefore, effective infection management will benefit from developing alternate strategies that critically depend on a better understanding of host-pathogen interactions. Both the host and pathogen undergo substantial metabolic adaptations that can either augment or hinder the immune system, affecting disease pathogenesis. Immune cell activation is regulated by metabolic rewiring after encountering pathogens [37]. These metabolic changes influence cytokine/chemokine expression, ROS production, and the functional properties of innate and adaptive immune cells. The study of how metabolism programs immune cell activity is termed immunometabolism [38] and a significant amount of foundational knowledge in this field comes from studies with MΦs. For example, proinflammatory MΦs exhibit a bias toward glycolysis, which generates intermediates required for proinflammatory cytokine and prostaglandin production, in addition to NADPH to fuel ROS. Conversely, anti-inflammatory MΦs depend on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) along with fatty acid oxidation (FAO) [39]. Metabolism also influences T cell, B cell, and epithelial cell responses during infection, highlighting the intricate association between cellular metabolism and functional activity [40].

On the other side of the coin, recent studies have demonstrated that bacterial metabolites also act on host cells to regulate homeostasis, differentiation, and proliferation [41, 42]. Bacterial metabolites can either stimulate host defense mechanisms or inhibit antimicrobial activity to mitigate or promote infection, respectively [43]. This review will summarize recent findings on metabolic alterations that occur during S. aureus infection, both from the bacterial and host perspectives, with a focus on innate immunity and possible implications on pathogenesis. We also discuss the impact of these metabolic pathways in other bacterial infections when information on S. aureus is lacking. The reader is directed to a recent comprehensive review on S. aureus metabolism [44], which is outside the scope of this work.

Immune cells alter their metabolic pathways following a pathogen encounter to tailor their effector functions [43, 45, 46]. Key pathways that generate intermediates and end products required for leukocyte proliferation, activity, and survival include glycolysis, pentose phosphate pathway (PPP), TCA, FAO, fatty acid synthesis (FAS), and amino acid metabolism (Fig. 1). Although these metabolic pathways generate different end products, they are interdependent for overall energy production.

Fig. 1.

Overview of major metabolic pathways. Glucose is transported into cells and converted to pyruvate during glycolysis, which can be metabolized to lactate or enter the tricarboxylic acid (TCA) cycle to generate NADH and FADH2. Fatty acid oxidation (FAO) produces NADH, FADH2, and acetyl-CoA of which acetyl-CoA enters the TCA cycle. NADH and FADH2 are utilized in the electron transport chain (ETC) for ATP production. Intermediates from glycolysis feed into the pentose phosphate pathway (PPP), which generates NADPH and precursors for nucleotides and amino acids. Citrate from the TCA cycle is used in lipid and amino acid synthesis. Fatty acids combine with glycerol to synthesize triglycerides and phospholipids in the cytosol (figure created using BioRender). GLUT, glucose transporter; MCT, monocarboxylate transporter; MPC, mitochondrial pyruvate carrier; CIC, citrate/isocitrate carrier; α-KG, alpha-ketoglutarate.

Fig. 1.

Overview of major metabolic pathways. Glucose is transported into cells and converted to pyruvate during glycolysis, which can be metabolized to lactate or enter the tricarboxylic acid (TCA) cycle to generate NADH and FADH2. Fatty acid oxidation (FAO) produces NADH, FADH2, and acetyl-CoA of which acetyl-CoA enters the TCA cycle. NADH and FADH2 are utilized in the electron transport chain (ETC) for ATP production. Intermediates from glycolysis feed into the pentose phosphate pathway (PPP), which generates NADPH and precursors for nucleotides and amino acids. Citrate from the TCA cycle is used in lipid and amino acid synthesis. Fatty acids combine with glycerol to synthesize triglycerides and phospholipids in the cytosol (figure created using BioRender). GLUT, glucose transporter; MCT, monocarboxylate transporter; MPC, mitochondrial pyruvate carrier; CIC, citrate/isocitrate carrier; α-KG, alpha-ketoglutarate.

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Glucose uptake from the extracellular environment initiates glycolysis in the cytosol where glucose is converted through ten enzymatic reactions to pyruvate. Glycolysis is an inefficient means of energy production, yielding only two ATP per unit of glucose, which raises the question of why cells would prefer this metabolic pathway, even in the presence of oxygen (aerobic glycolysis). This is because glycolytic intermediates are also used to synthesize nucleotides and amino acids as well as regulate ROS production, making this a preferred pathway for proinflammatory cells that require robust biomolecule synthesis for antibacterial activity [47]. Pyruvate is the final product of glycolysis and is either actively transported into mitochondria to initiate the TCA cycle or converted to lactate in the cytosol and excreted to maintain glycolytic flux and NAD+/NADH levels. Under hypoxic conditions, lactate production is increased due to diminished electron transport chain (ETC) activity that requires oxygen. The PPP diverts glycolytic intermediates to produce nucleotides and amino acids and also generates NADPH, which is critical for maintaining cellular redox balance and fueling NADPH oxidase activity as well as cholesterol and fatty acid synthesis [48]. The TCA cycle occurs in mitochondria and utilizes pyruvate-generated acetyl-CoA to initiate the cycle, generating NADH and FADH2 that drive the ETC to produce ATP. Like glycolysis, TCA intermediates are used for amino acid and lipid synthesis [49]. FAO is the process of catabolizing fatty acids into acetyl-CoA, which can feed into the TCA cycle and ETC to generate ATP.

Other biosynthetic pathways include FAS that requires citrate, whereas branched chain fatty acid production uses amino acids for elongation. Furthermore, glycerol is used as a substrate for triglycerides and phospholipids that are crucial components of cellular membranes and organelles. Apart from being precursors for protein synthesis, amino acids can be shuttled into other metabolic pathways. For example, glutamine and aspartate are used for de novo nucleotide biosynthesis and glutamine is converted to α-ketoglutarate, which feeds into the TCA cycle [50]. Also, L-arginine is used by inducible nitric oxide synthase (iNOS) to generate the free radical nitric oxide that exerts antimicrobial activity through protein nitrosylation, lipid peroxidation, and DNA damage [51]. Given the interconnection between these metabolic pathways (Fig. 1), several studies have identified their importance in regulating the immune response against S. aureus infection and disease pathogenesis, which are discussed below.

Increased glycolytic activity is an essential pathway for MΦ, dendritic cell, and PMN activation in response to proinflammatory stimuli such as Toll-like receptor and other pattern recognition receptor ligands [52‒56]. For example, lipopolysaccharide (LPS) treatment of MΦs leads to hypoxia-inducible factor 1a (HIF-1a) stabilization, which promotes the transcription of several genes encoding glycolytic enzymes including hexokinase 2 (HK2) and phosphofructokinase as well as glucose transporters (i.e., GLUT3) to increase IL-1β production [57‒60]. Recently, MΦ glycolytic activity was shown to induce antibiotic tolerance in S. aureus by limiting glucose and ATP availability for the bacterium [61]. This was attributed to the ability of S. aureus α-toxin to activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome since antibiotic efficacy was increased in a mouse bacteremia model when NLRP3 was inhibited. This highlights a “tug of war,” where glycolysis is typically required for MΦ proinflammatory activity, yet it places pressure on S. aureus to become more metabolically dormant to evade antibiotics that require active cell wall and protein biosynthesis for efficacy. However, since most S. aureus infections are eventually cleared, it remains to be determined whether this phenotype is selective for specific antibiotic classes, how the timing between infection and antibiotic dosing influences antibiotic sensitivity versus tolerance, and how other immune effector mechanisms compensate for the acquisition of S. aureus antibiotic tolerance within the MΦ niche.

Keratinocytes defend against cutaneous infections by providing physiological and immunological barriers in the skin. S. aureus infection enforces metabolic stress on keratinocytes and induces glycolysis through HIF-1a activation to promote IL-1β and IL-18 expression [62] (Fig. 2a). Interestingly, this response was dependent on bacterial glycolysis since neither a S. aureus glycolytic mutant (Δpyk) nor PAMPs alone were able to promote keratinocyte glycolysis. Hexokinase (HK) represents the first irreversible step in glycolysis, which is inhibited by 2-deoxyglucose (2-DG), and 2-DG typically suppresses proinflammatory responses in many leukocyte populations [63, 64]. However, 2-DG treatment of mice infected with wild-type (WT) S. aureus resulted in larger skin lesions and delayed wound healing with no change in bacterial abundance. Interestingly, animals infected with Δpyk had significantly lower bacterial burden and minimal dermonecrosis compared to WT bacteria, highlighting the importance of S. aureus glycolysis in promoting cutaneous infection. While bacterial glycolysis was critical for establishing infection, the larger skin lesions observed with 2-DG treatment suggest that host glycolysis is also required to control excessive inflammation but not S. aureus growth. It would be interesting to dissect whether glycolytic activity in keratinocytes versus invading leukocytes is responsible for this phenotype and whether inhibiting glycolysis after bacterial infection has any effect on pathology.

Fig. 2.

Modulation of glycolysis during S. aureus infection. a Planktonic S. aureus promotes the expression of glycolytic enzyme (HK2 and PFK1) and proinflammatory (IL-1β) genes by increasing HIF-1a in mammary epithelial cells and keratinocytes. b Biofilms elicit a distinct metabolic response, whereby lactate released by S. aureus biofilm is transported into G-MDSCs and MФs, where it inhibits HDAC11, a negative regulator of HDAC6. This results in unchecked HDAC6 activity, which is a transcriptional inducer of IL-10, leading to elevated IL10 production to promote biofilm persistence. During S. aureus biofilm infection, host lactate biosynthesis does not affect IL-10 levels (figure created using BioRender). GLUT, glucose transporter; MCT1, monocarboxylate transporter 1; HIF-1α, hypoxia-inducible factor 1α; HDAC, histone deacetylase.

Fig. 2.

Modulation of glycolysis during S. aureus infection. a Planktonic S. aureus promotes the expression of glycolytic enzyme (HK2 and PFK1) and proinflammatory (IL-1β) genes by increasing HIF-1a in mammary epithelial cells and keratinocytes. b Biofilms elicit a distinct metabolic response, whereby lactate released by S. aureus biofilm is transported into G-MDSCs and MФs, where it inhibits HDAC11, a negative regulator of HDAC6. This results in unchecked HDAC6 activity, which is a transcriptional inducer of IL-10, leading to elevated IL10 production to promote biofilm persistence. During S. aureus biofilm infection, host lactate biosynthesis does not affect IL-10 levels (figure created using BioRender). GLUT, glucose transporter; MCT1, monocarboxylate transporter 1; HIF-1α, hypoxia-inducible factor 1α; HDAC, histone deacetylase.

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S. aureus has also been shown to increase glycolysis in mammary epithelial cells through a 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3)-dependent mechanism to augment HIF-1a and ROS levels [65]. This response was negated by blocking host glycolysis with either 2-DG or a PFKFB3 antagonist (PFK15). In a mouse model of S. aureus mastitis, PFK15 treatment attenuated inflammation resulting in reduced tissue damage and bacterial burden, suggesting a deleterious effect of glycolytic activity [65]. These findings reiterate the complexities of host cell glycolysis in dictating S. aureus infection outcome (Fig. 2a).

S. aureus small colony variants (SCVs) are often associated with persistent infections [66]. SCVs are slow growing, have a pinpoint colony size, and possess mutations in various genes, especially those associated with electron transport. Because of these mutations, SCVs have altered metabolism, with increased glycolysis and decreased TCA cycle activity and respiration [67]. Both a prototypic SCV (ΔhemB) and WT S. aureus induced glycolysis in keratinocytes, resulting in ROS production and necroptosis, unlike their heat-killed counterparts [68]. Interestingly, necroptosis had no effect on ΔhemB growth and instead induced a metabolic adaptation to augment fumC expression, an enzyme that degrades fumarate. Since fumarate is a negative regulator of glycolysis, increased fumC expression promoted glycolysis, providing permissive conditions for bacterial survival [68]. This study indicates that S. aureus can actively induce metabolic pathways that are beneficial for bacterial persistence in host cells.

Neutrophils rely on glycolysis for energy production since they have fewer mitochondria, and as such, inhibiting mitochondrial respiration does not impact ATP production [69‒72]. In contrast, blocking glycolysis with 2-DG impairs PMN phagocytosis and ROS production, and thereby bacterial killing, highlighting the importance of glycolysis for their antimicrobial properties [73, 74]. The glycolytic intermediate glucose-6-phosphate fuels the PPP to generate NADPH, which is used by NADPH oxidase for ROS production in activated PMNs [75]. Pyruvate kinase M2 (PKM2), one of the rate-limiting glycolytic enzymes that converts phosphoenolpyruvate to pyruvate, was shown to regulate PMN ROS production without affecting phagocytosis during S. aureus infection [76]. Upon activation by the endogenous regulator fructose-1,6-bisphosphate, PKM2 forms a tetramer that promotes high glycolytic activity that is essential for ROS production. However, in the absence of an activator, PKM2 assumes a monomeric or dimeric form that localizes to the nucleus and regulates transcription factor activation, including HIF-1a- and signal transduction and activator of transcription proteins [77]. NADPH oxidase activation requires protein kinase C-dependent phosphorylation, which is induced by diacylglycerol (DAG) [78]. DAG is synthesized from two independent pathways, namely, (1) phosphatidylinositol 4,5-bisphosphate hydrolysis by phospholipase C and (2) de novo synthesis from the glycolytic intermediate dihydroxyacetone phosphate [79]. While DAG produced from both pathways contributes to ROS production by PMNs, PKM2 regulates ROS release in activated PMNs by controlling de novo DAG synthesis. PKM2 was important for bacterial containment in S. aureus peritonitis and cutaneous infection models, where PKM2-deficient mice displayed higher bacterial burden and delayed wound healing compared to WT animals. An earlier study reported defective PMN pyruvate kinase activity in a patient experiencing recurrent S. aureus infections [80] and together, these studies demonstrate that glycolytic intermediates and the PPP are critical for PMN ROS production and subsequent antimicrobial activity.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that possess anti-inflammatory activity and are associated with various pathological conditions such as infection, cancer, and autoimmune diseases [81‒84]. MDSCs are characterized into two major subsets, namely, granulocytic (G-MDSCs) or monocytic (M-MDSCs), based on their similarities with PMNs and monocytes, respectively [85]. In general, G-MDSCs exert their suppressive activity through ROS and arginase 1 (Arg-1), whereas M-MDSCs use iNOS and anti-inflammatory cytokines such as IL-10 and TGF-β to inhibit T cell responses [86‒88]. G-MDSCs play a pathological role in mouse models of S. aureus infection by inhibiting proinflammatory responses, leading to increased bacterial survival [21, 89–93] and G-MDSCs have also been shown to accumulate at the site of prosthetic joint infection (PJI) in humans [94]. A recent study reported that glycolysis was important for driving G-MDSC maturation into PMNs in a mouse model of systemic S. aureus infection, although this had no effect on bacterial burden [95]. However, these observations were made in MDSCs distant from the infection site, which may affect their properties since MDSCs were not in direct contact with bacteria. T cells are important for generating protective immune responses to S. aureus [96, 97], which can be inhibited by MDSCs [91]. T cell proliferation during S. aureus infection was reported to be inhibited by lactate released from MDSCs, which prevented NAD+ regeneration and glycolysis that is a hallmark of activated T cells [98]. However, the effects of lactate during S. aureus infection are likely influenced by the tissue niche and growth state of bacteria since our laboratory has shown that lactate production by host cells had no effect on S. aureus biofilm infection, but rather S. aureus-derived lactate was a potent driver of G-MDSC anti-inflammatory activity by eliciting IL-10 production [99]. Therefore, additional studies are needed to better understand the G-MDSC-pathogen metabolic dynamic in distinct niches of S. aureus infection.

S. aureus can modulate the host immune response by secreting metabolites in the infection milieu. As mentioned earlier, our laboratory recently showed that lactate produced by S. aureus biofilm promoted IL-10 production by MΦs and G-MDSCs [99]. We leveraged S. aureus lactate dehydrogenase mutants and a monocarboxylate transporter 1 (MCT1) inhibitor to demonstrate that biofilm-derived lactate was transported into G-MDSCs and MΦs to inhibit histone deacetylase 11 (HDAC11). Under normal conditions, HDAC11 interacts with HDAC6 to inhibit IL-10 transcription [100]; however, during S. aureus biofilm infection, bacterial-derived lactate blocks this interaction to promote IL-10 transcription in G-MDSCs and MΦs (Fig. 2b). S. aureus lactate dehydrogenase mutants displayed less survival than WT bacteria with a concomitant decrease in anti-inflammatory G-MDSCs and increased PMN and monocyte infiltrates. This phenotype was shown to be IL-10-dependent, confirming the action of lactate on promoting IL-10 production, which is important for polarizing the anti-inflammatory biofilm milieu [21]. However, ChIP-seq demonstrated that S. aureus lactate also affected the expression of additional genes, revealing a larger footprint of biofilm-derived lactate on host responses. D-lactate levels were elevated in the synovial fluid of PJI patients compared to individuals with aseptic joint revision [99] and lactate has been shown to be a sensitive marker for diagnosing PJI in humans [101‒103], supporting the importance of bacterial lactate metabolism in the setting of biofilm infection.

Host lactate also plays a role in shaping leukocyte responses during various pathological conditions such as infection and cancer [104‒106]. In LPS-activated MΦs, lactate was shown to suppress proinflammatory cytokine production via G protein-coupled receptor 81 (GPR81)-mediated signaling [107]. Lactate also impaired TLR4-mediated inflammasome activation through GPR81 signaling in MΦs and monocytes, and lactate administration attenuated inflammation and disease severity in models of acute pancreatitis and liver injury [108]. Lactate has been shown to modify mitochondrial antiviral-signaling protein to prevent its mitochondrial localization and interaction with RIG-1, thereby attenuating type I interferon production [109]. These data suggest that host lactate can target multiple mechanisms to regulate leukocyte proinflammatory activity.

Collectively, these studies highlight the importance of glycolysis, lactate, and glycolytic intermediates produced by both the host and S. aureus in shaping immune responses. However, it is clear that the effects of host versus pathogen metabolism are context-dependent. On the one hand, glycolysis in keratinocytes and PMNs drives proinflammatory responses to kill planktonic S. aureus, whereas in biofilm, bacterial-derived lactate is a major signal that leads to epigenetic remodeling in G-MDSCs and MΦs to promote IL-10 production that ensures bacterial persistence. Although the importance of glycolysis has been studied in keratinocytes, epithelial cells, and PMNs during S. aureus infection, less information is available in other key cell types involved in S. aureus infection, such as MΦs, G-MDSCs, and T cells. In addition, how host glycolysis is altered during biofilm infection requires further investigation as most of our current knowledge is derived from planktonic infections. Another enigma that remains to be understood relates to the dichotomy in infectious outcomes between S. aureus planktonic versus biofilm infection when proinflammatory cytokine expression is a hallmark of both. In the case of planktonic S. aureus infection, this response is typically linked to bacterial clearance [110, 111]. However, proinflammatory mediators are also produced during biofilm infection and although they have been shown to play a role in preventing S. aureus outgrowth [112‒115], infection persists. Although seemingly counterintuitive, this may be explained, in part, by the fact that proinflammatory mediators are important for G-MDSC expansion and suppressive activity [85, 116], and S. aureus biofilm infections are typified by a large G-MDSC infiltrate [90, 92, 94, 117–119]. In addition, the large bacterial biomass associated with biofilm elicits continued proinflammatory mediator release, which would perpetuate the G-MDSC inhibitory loop. Another contributing factor is the induction of a robust IL-10 response during S. aureus biofilm infection that promotes infection persistence [93, 99]. Therefore, a better understanding of how leukocytes are seemingly refractory to the antimicrobial actions of proinflammatory cytokine stimulation during S. aureus biofilm infection may help to “flip the switch” to reprogram cells for enhanced bactericidal activity [120].

Toll-like receptor ligands such as LPS induce glycolytic metabolism in proinflammatory MΦs, leading to break points in the TCA cycle [121]. This is typified by accumulation of the TCA cycle intermediates α-ketoglutarate, fumarate, itaconate, succinate, and citrate, which can modulate the immune response [122]. For example, succinate and α-ketoglutarate inhibit prolyl hydroxylases, proteins that bind the transcription factor HIF-1a, and promote its degradation under normoxia [123, 124]. However, during aerobic glycolysis, HIF-1a stabilization promotes the transcription of glycolytic genes, which acts in a positive feedback loop to augment glycolysis and IL-1β production in MΦs [63]. Succinate dehydrogenase (SDH), also known as mitochondrial complex II, is a TCA cycle enzyme that catalyzes the conversion of succinate to fumarate and is a key player in regulating MΦ proinflammatory gene expression following LPS stimulation by boosting succinate oxidation and mitochondrial ROS [125]. Inhibition of SDH reduced IL-1β concomitant with increased IL-10 and IL-1RA expression, thereby blocking the proinflammatory phenotype of LPS-induced MΦs. Citrate, another TCA cycle intermediate, is exported from mitochondria to the cytoplasm via citrate carrier where it promotes NO and prostaglandin production by MΦs in response to IFN-γ and TNF [126].

The TCA cycle break that ensues during glycolysis effectively reduces OxPhos substrates, highlighting how metabolic diversion can augment glycolysis to provide intermediates for the numerous biosynthetic reactions that are a hallmark of proinflammatory MΦs and PMNs. However, it is important to note that the TCA cycle is not completely inactive when cells are highly glycolytic; anaplerotic reactions can occur from amino acids feeding into various points in the TCA cycle, most notably glutamine conversion to α-ketoglutarate. This highlights metabolic plasticity and that pathways are in a constant state of flux, adapting to the energetic requirements of the leukocyte and integrating exogenous signals from the infectious milieu to tailor immune cell polarization.

Itaconate, a metabolite derived from the TCA cycle intermediate cis-aconitate by the enzyme IRG1, is a competitive inhibitor of SDH due to its structural similarity with succinate. IRG1 deletion in MΦs resulted in unchecked SDH activity and heightened proinflammatory responses concomitant with increased HIF-1a activation [127]. The IRG1-SDH axis also plays a central role in regulating immune tolerance and trained immunity during LPS-induced sepsis [128]. 4-Octyl itaconate, an itaconate derivative, inhibited glycolysis in LPS-activated MΦs by targeting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thereby suppressed LPS-induced metabolic changes required for IL-1β and iNOS expression [129]. Further, Qin et al. [130] revealed that the glycolytic enzymes fructose-bisphosphate aldolase A (ALDOA), GAPDH, and lactate dehydrogenase A (LDHA) are modified by itaconate to inhibit glycolysis and promote MΦ anti-inflammatory activity [130]. Together, these studies suggest that itaconate utilizes multiple mechanisms to modulate MΦ activation.

In terms of S. aureus, itaconate was elevated in the bronchoalveolar lavage fluid during acute lung infection, concomitant with IRG1 induction [131]. Itaconate inhibited S. aureus aldolase activity, effectively blocking glycolysis, a preferred metabolic pathway for the bacterium during infection. This induced S. aureus metabolic adaptation, typified by increased extracellular polysaccharide production, reduced ribosomal activity, and decreased virulence factor expression, consistent with a transition to biofilm growth. This is supported by the finding that S. aureus acquired antibiotic tolerance in the presence of host-derived itaconate, which is a hallmark of biofilm formation. Like S. aureus, P. aeruginosa also exploits host itaconate during lung infection where it degrades and metabolizes itaconate to produce energy [132]. Although these studies reflect the ability of diverse bacterial species to utilize host-derived itaconate to their advantage, itaconate also influences leukocyte activity to prevent S. aureus clearance. For example, bacterial burden was significantly lower in Irg1−/− compared to WT mice in a S. aureus pneumonia model. This was attributed to itaconate production by PMNs, which inhibited their glycolytic activity and ROS production to impair bacterial killing [133] (Fig. 3a). In contrast to these anti-inflammatory effects, itaconate benefits the host during Mycobacterium tuberculosis (Mtb) and Klebsiella pneumonia infection by controlling excessive inflammation and limiting tissue damage [134, 135]. Likewise, itaconate can exert direct antibacterial activity by inhibiting the glyoxylate cycle in Pseudomonas indigofera, Salmonella enterica, and Mtb [136‒139]. Therefore, the effector functions of itaconate during infection are context-dependent given its antibacterial properties and ability to induce adaptations in bacteria and/or modulate leukocyte activity.

Fig. 3.

Effect of TCA cycle intermediates during S. aureus infection. aS. aureus infection induces immune responsive gene 1 (IRG1)-mediated itaconate production in neutrophils. Itaconate inhibits ROS and glycolysis to attenuate neutrophil anti-bacterial activity. b During S. aureus infection, fumarate accumulation inhibits histone demethylase KDM5 to augment proinflammatory gene expression. S. aureus fumarate hydratase (fumC) is increased in SCVs that arise during infection, which degrades fumarate to promote glycolysis and impair proinflammatory gene expression through epigenetic modifications (figure created using BioRender). ROS, reactive oxygen species; α-KG, alpha-ketoglutarate; KDM5, lysine demethylase 5.

Fig. 3.

Effect of TCA cycle intermediates during S. aureus infection. aS. aureus infection induces immune responsive gene 1 (IRG1)-mediated itaconate production in neutrophils. Itaconate inhibits ROS and glycolysis to attenuate neutrophil anti-bacterial activity. b During S. aureus infection, fumarate accumulation inhibits histone demethylase KDM5 to augment proinflammatory gene expression. S. aureus fumarate hydratase (fumC) is increased in SCVs that arise during infection, which degrades fumarate to promote glycolysis and impair proinflammatory gene expression through epigenetic modifications (figure created using BioRender). ROS, reactive oxygen species; α-KG, alpha-ketoglutarate; KDM5, lysine demethylase 5.

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Fumarate, another TCA cycle intermediate, participates in the induction of trained immunity in monocytes [140]. Specifically, fumarate inhibits the KDM5 family of histone demethylases, leading to enhanced histone H3 lysine 4 methylation to regulate proinflammatory cytokine gene expression [140]. Dimethyl fumarate (DMF), a fumarate derivative, succinylates the catalytic cysteine residue of GAPDH to suppress glycolysis, effectively mediating anti-inflammatory effects in myeloid and lymphoid cells [141]. Moreover, both DMF and fumarate modify gasdermin D to block its interaction with caspase-1, which is required for gasdermin D cleavage and oligomerization to induce cell death [142]. DMF treatment revealed beneficial effects in mouse models of LPS shock and experimental autoimmune encephalitis by its ability to inhibit gasdermin D [142].

While these studies suggest that fumarate can control both pro- and anti-inflammatory activity, fumarate was found to induce trained immunity and protect against secondary infection in a model of S. aureus cutaneous infection [68] (Fig. 3b). However, S. aureus SCVs that accumulate during infection upregulate fumarate hydratase (fumC) that converts fumarate to malate, effectively reducing fumarate levels in the infected skin. This decrease in fumarate allows SCVs to circumvent trained immunity, which prevents protection against subsequent bacterial challenge. Increased fumC expression has also been observed in S. aureus clinical isolates from cystic fibrosis and atopic dermatitis subjects, suggesting that fumarate is an important target for S. aureus pathogenesis [143, 144] (Fig. 3b).

Recently, fumarate, along with itaconate and arginosuccinate, was found to accumulate in LPS-activated MΦs to mediate protein succincylation [145]. Fumarate hydratase (FH) inhibition or genetic deletion increased intracellular fumarate levels resulting in TCA cycle rewiring, suppression of mitochondrial respiration, and increased membrane potential. Mitochondrial dysfunction following FH inhibition led to mitochondrial RNA release, activating the intracellular RNA sensors Toll-like receptor 7 (TLR7), melanoma differentiation-associated protein 5 (MDA5), and retinoic acid-inducible gene I (RIG-I) to induce interferon-β production. Similar findings were reported in another study, where FH loss resulted in altered mitochondrial morphology and mitochondrial DNA release into the cytosol that was sensed by cyclic GMP-AMP synthase stimulator of interferon genes to induce type I interferon production [146]. Together, these results suggest that fumarate metabolism plays an important role in regulating MΦ activation. However, additional studies are needed to explore how this pathway influences S. aureus infection.

NADH from the TCA cycle enters OxPhos to transfer electrons in the ETC, where ATP is generated by ATP synthase using electron flow. In MΦs, LPS stimulation arrests ETC-dependent ATP production and succinate oxidation increases mitochondrial transmembrane potential, leading to reverse electron transport-mediated ROS synthesis [125]. This ROS can further activate the inflammasome or exert anti-microbial activity. In PMNs, mitochondrial ROS and NET production were shown to be dependent on ETC complexes during S. aureus infection [147]. Specifically, PMN bactericidal activity was attenuated when mitochondrial ROS was inhibited using either the complex III inhibitor antimycin A or the antioxidant mitoTEMPO. On the other hand, anti-inflammatory MΦs exhibit an OxPhos bias [148]. For example, we have shown that S. aureus biofilm skews monocytes/MΦs toward OxPhos over glycolysis in a mouse model of S. aureus PJI [118] (Fig. 4). Inhibiting oxidative metabolism in monocytes/MΦs using targeted nanoparticles containing the ATP synthase inhibitor oligomycin reprogrammed cellular metabolism in vivo, leading to heightened proinflammatory cytokine production and significant reductions in S. aureus burden. Further, monocyte/MΦ metabolic reprogramming in combination with systemic antibiotics effectively cleared an established biofilm infection that represents the most challenging treatment scenario [118]. This study also showed that monocyte/MΦ metabolic reprogramming influences G-MDSC metabolism, emphasizing the importance of metabolic crosstalk, not only between different leukocyte populations but also S. aureus. Based on these findings, it is evident that the effects of OxPhos during S. aureus infection are cell- and context-dependent. In addition, the growth phase of bacteria also likely plays a role, whether organisms are in a planktonic or biofilm state.

Fig. 4.

OxPhos-mediated metabolic reprogramming during S. aureus biofilm infection. During S. aureus biofilm infection, monocyte and MФ metabolism is reprogrammed to utilize oxidative phosphorylation (OxPhos) to promote anti-inflammatory activity and biofilm persistence. Inhibition of ATP synthase with oligomycin-loaded nanoparticles reprograms monocyte metabolism to promote ROS production and proinflammatory gene expression. This change in monocyte metabolism also alters G-MDSC metabolism. These metabolic alterations decreased bacterial burden and increased S. aureus susceptibility to systemic antibiotics to mitigate established biofilm infection (figure created using BioRender). G-MDSCs, granulocytic-myeloid-derived suppressor cells; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; HIF-1a, hypoxia-inducible factor 1a.

Fig. 4.

OxPhos-mediated metabolic reprogramming during S. aureus biofilm infection. During S. aureus biofilm infection, monocyte and MФ metabolism is reprogrammed to utilize oxidative phosphorylation (OxPhos) to promote anti-inflammatory activity and biofilm persistence. Inhibition of ATP synthase with oligomycin-loaded nanoparticles reprograms monocyte metabolism to promote ROS production and proinflammatory gene expression. This change in monocyte metabolism also alters G-MDSC metabolism. These metabolic alterations decreased bacterial burden and increased S. aureus susceptibility to systemic antibiotics to mitigate established biofilm infection (figure created using BioRender). G-MDSCs, granulocytic-myeloid-derived suppressor cells; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; HIF-1a, hypoxia-inducible factor 1a.

Close modal

Both FAO and FAS are important for regulating leukocyte function (Fig. 5). For example, fatty acid uptake and triglyceride synthesis were increased in LPS-activated proinflammatory MΦs, whereas lipolysis was repressed [149]. In addition, inhibition of MΦ FAS decreased inflammation and MΦ recruitment in vivo [150]. This study showed that FAS was necessary for Rho GTPase trafficking and membrane remodeling to facilitate MΦ inflammatory signaling. In contrast, initial reports with etomoxir, an inhibitor of mitochondrial carnitine palmitoyl-transferase 1 (Cpt1), suggested that FAO was important for anti-inflammatory MΦ polarization in response to IL-4 [151]. However, subsequent studies using Cpt1a-deficient MΦs have shown that the anti-inflammatory effects of etomoxir are mediated through altered CoA levels and not FAO [152]. Again, this highlights the complexity of metabolism and the need for cleaner systems such as genetic deletion rather than relying on inhibitors alone to understand the importance of metabolism in shaping immune responses.

Fig. 5.

Role of fatty acids in S. aureus infection. Long-chain fatty acids are imported into mitochondria through CPT1a and are oxidized to form acetyl-CoA, acyl-CoA, NADH, and FADH2. NADH and FADH2 provide electrons for the electron transport chain (ETC), while acetyl-CoA enters the TCA cycle. Citrate from the TCA cycle is transported to the cytosol, where it is converted to acetyl-CoA to drive fatty acid synthesis. Exogenous fatty acids can augment neutrophil antibacterial activity. Etomoxir inhibition of Cpt1a-dependent FAO impairs S. aureus killing resulting in increased infectious burden (figure created using BioRender). α-KG, alpha-ketoglutarate; CIC, citrate/isocitrate carrier; CPT1a, carnitine palmitoyltransferase 1a.

Fig. 5.

Role of fatty acids in S. aureus infection. Long-chain fatty acids are imported into mitochondria through CPT1a and are oxidized to form acetyl-CoA, acyl-CoA, NADH, and FADH2. NADH and FADH2 provide electrons for the electron transport chain (ETC), while acetyl-CoA enters the TCA cycle. Citrate from the TCA cycle is transported to the cytosol, where it is converted to acetyl-CoA to drive fatty acid synthesis. Exogenous fatty acids can augment neutrophil antibacterial activity. Etomoxir inhibition of Cpt1a-dependent FAO impairs S. aureus killing resulting in increased infectious burden (figure created using BioRender). α-KG, alpha-ketoglutarate; CIC, citrate/isocitrate carrier; CPT1a, carnitine palmitoyltransferase 1a.

Close modal

The role of FAO and FAS has been studied in various infections, such as Mtb and S. enterica [153‒156]; however, whether these metabolic pathways influence S. aureus infection remains relatively unknown. While some omega-3 fatty acids have been shown to be antimicrobial and inhibit biofilm formation [157, 158], their effects on immune responses to S. aureus remain to be defined. In a mouse model of S. aureus sepsis, animals fed a polyunsaturated fatty acid diet displayed increased survival and PMN abundance compared to mice receiving a saturated fatty acid diet, although the exact role of polyunsaturated fatty acids in this setting is unknown [159]. Omega-3 fatty acids, either alone or in combination with vancomycin, reduced bacterial burden in the bone and implant concomitant with less TNF and IL-6 production in a rat model of S. aureus implant-associated osteomyelitis [160] (Fig. 5). Recently, a Cpt1a variant with reduced enzymatic activity has been identified in humans and linked to susceptibility to various infections, including S. aureus [161]. Cpt1a inhibition with etomoxir increased bacterial burden in a mouse model of S. aureus pneumonia (Fig. 5) and impaired PMN recruitment and fatty acid-mediated mitochondrial bioenergetics during Acinetobacter baumannii infection. In addition, FAO was found to be critical for amplifying chemotactic signals and PMN migration using both Cpt1a inhibitors and fatty acid supplementation [161]. Collectively, these findings raise the possibility that dietary fatty acids may influence PMN trafficking and potentially provide some benefit during S. aureus infection. However, as with any metabolic node, the net flux through other pathways, not to mention the metabolic status of bacteria, will likely dictate efficacy.

Amino acid metabolism is important for both innate and adaptive immune cells [162, 163]. Glutamine flux into the TCA cycle is associated with anti-inflammatory MΦ polarization following IL-4 exposure, while the aspartate-arginosuccinate shunt is involved in proinflammatory MΦ programming by LPS [164]. Both Arg-1 and iNOS utilize arginine as a substrate to produce ornithine and nitric oxide, respectively. While iNOS is induced in proinflammatory MΦs to control bacterial growth, Arg-1 is associated with MΦ anti-inflammatory activity to promote fibrosis and wound healing via the action of polyamines that are synthesized from ornithine [51]. Polyamines are abundant in S. aureus abscesses and interfering with polyamine synthesis using difluoromethylornithine (DFMO), a potent inhibitor of ornithine decarboxylase, resulted in increased bacterial burden and decreased survival in mouse models of S. aureus sepsis and skin abscesses [165]. Additionally, skin lesions in DFMO-treated mice exhibited limited fibrosis, revealing an essential role for polyamines in wound healing. In a mouse model of sepsis, competitive inhibition of arginase with S-(2-boronoethyl)-L-cysteine protected against S. aureus infection, resulting in increased survival [166]. However, no phenotypes were observed when Arg-1 was deleted in myeloid cells using Arg-1fl/fl Tie-2Cre mice in either biofilm models of S. aureus PJI or catheter-associated infection, whereas effects were detected in abscesses that have characteristics of planktonic growth [167]. Together, these results demonstrate that the role of Arg-1 and subsequent polyamine production in myeloid cells in response to S. aureus is context-dependent.

Differential preferences for iNOS and Arg-1 activity also typify MDSC subtypes, which are utilized by M-MDSCs and G-MDSCs, respectively, to mediate immunosuppression [168, 169]. Another amino acid that MDSCs utilize to inhibit T cell activation is tryptophan. Tryptophan is an essential amino acid and substrate of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes tryptophan catabolism [170]. IDO1 expression by MDSCs reduces local tryptophan concentrations, thereby suppressing T cells that require tryptophan for proliferation [171]. Tryptophan catabolism also produces the immunoregulatory molecules kynurenine and serotonin, which have been reported to affect leukocyte function during infection. For example, human MΦs and dendritic cells produce kynurenine in an IDO1-dependent manner in response to Listeria monocytogenes, where kynurenine and other tryptophan catabolites promoted antimicrobial activity [172]. In addition, accumulation of tryptophan metabolites, such as 3-hydroxy-DL-kynurenine and alpha-picolinic acid, protected vascular allografts against methicillin-resistant S. aureus, S. epidermidis, E. coli, and P. aeruginosa [173, 174]. Collectively, these studies indicate that various products of amino acid metabolism can influence the pro- versus anti-inflammatory attributes of leukocyte populations that shape the infection milieu. This is likely important in tissues where glucose becomes limiting, such as chronic infections that are poorly perfused, where both the host and bacteria must metabolically adapt to utilize different carbon sources, such as amino acids resulting from protein degradation for de novo energy production via the pathways described above.

Given the link between bacterial infections and metabolic diseases such as diabetes [175, 176], the potential efficacy of metabolic drugs to control infection and associated pathology has received increasing attention. Diabetic individuals are at increased risk for severe S. aureus infections, primarily in the skin [177‒179] that can progress to bacteremia [180]. This is also observed in mouse models, where S. aureus skin infection was more severe in diabetic mice and correlated with diminished ROS production, PMN activation, and impaired humoral responses compared to nondiabetic mice [181, 182]. S. aureus burden and infection severity were also significantly increased in abscesses and osteomyelitis following streptozotocin-induced hyperglycemia [183, 184]. Collectively, these findings support the fact that S. aureus thrives in a glucose-rich environment, which is known to induce a wide array of virulence factors that can augment host tissue damage and leukocyte dysfunction [183, 185, 186].

Targeting glycolytic enzymes such as HK, PFKFB3, and pyruvate kinase have shown benefit in attenuating inflammation during immune-mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis and rheumatoid arthritis [187‒191]. Similarly, GLUT1, HK, and phosphofructokinase are promising targets for cancer treatment [192]. These findings support the importance of glycolytic flux during chronic diseases, and it would be interesting to explore these drugs in the context of S. aureus infections. Metformin, a compound widely used in diabetes to reduce glucose levels, was shown to inhibit Mtb growth in MΦs and synergize with conventional anti-tuberculosis chemotherapy to control Mtb infection in mice [193]. This was further evaluated in human cohorts, where metformin improved clinical outcome and decreased disease severity. A recent study reported that diabetic patients taking metformin experienced significantly less mortality following S. aureus bacteremia compared to control groups [194], suggesting a beneficial role for metabolic intervention and disease outcome, although additional studies are needed. Other notable drugs that control metabolism include methotrexate, rapamycin, and DMF that target dihydrofolate reductase, mammalian target of rapamycin (mTOR), and Kelch-like ECH-associated protein 1 (KEAP1), respectively [195‒197]. However, there are currently no metabolic compounds approved or in clinical trials for S. aureus infection. Given the importance of various metabolic pathways in altering immune responses to S. aureus, drugs that selectively target key pathways, from either the host or bacterial perspectives, would be interesting to explore. As discussed previously, using oligomycin or fatty acids as adjunct therapy with antibiotics may improve treatment outcomes compared to antibiotics alone [118, 195]. An added advantage of utilizing drugs that target metabolic pathways is a lower chance of bacteria-developing resistance [198] and their well-documented safety record. This remains an area for future exploration in the context of S. aureus, particularly considering the myriad of tissues that the organism can exploit in humans and associated metabolic diversity in each niche.

Unlike many other bacterial infections that exhibit tropism for a particular tissue, S. aureus can adapt and survive within multiple cell types and locations in the body [199]. Our understanding of how S. aureus and leukocyte metabolism shapes infectious outcomes and the consequences of host-pathogen metabolic crosstalk has been expanding in recent years [27, 120, 200, 201]. Nevertheless, specific influences of diverse clinical isolates, infection sites, and planktonic versus biofilm modes of growth on leukocyte metabolism remain relatively unexplored. The ability of S. aureus to adapt to different metabolic intermediates during infection (i.e., itaconate) or actively secrete metabolites to thwart productive antibacterial immune responses (i.e., lactate) highlights the extensive metabolic flexibility of the organism. Advancements in the field using techniques that measure metabolism at the single-cell level, such as single-cell energetic metabolism by profiling translation inhibition (SCENITH) and Met-Flow [202, 203], will improve our understanding of metabolic interactions between multiple leukocyte populations and at the tissue level. However, these methods measure metabolism at the protein, not the metabolite level, which requires conventional mass spectrometry approaches. The development of sensors that can monitor metabolites is expanding [204, 205] and real-time monitoring and spatiotemporal organization of metabolites during disease conditions will extend our understanding of metabolite shuttling and subsequent cellular responses. Recently, a correlative imaging approach, metaFISH [206], was developed by combining matrix-assisted laser desorption ionization-mass spectrometry imaging with fluorescence in situ hybridization, allowing the spatial distribution of metabolites to be identified in a tissue section. This is a significant advance to reveal the complex relationship of metabolites to host defense, cell-cell communication, and nutritional exchange during host-pathogen interactions. Integrating data from various animal models with findings from human samples from both the S. aureus and leukocyte perspectives will be essential to gain a better understanding of the metabolic complexity of infectious niches and developing novel therapeutic approaches to combat this important human pathogen.

The authors have no conflicts of interest to declare.

This work was supported by 3P01AI083211 Project 4 and R21 AI174381-01A1 to Tammy Kielian.

Prabhakar Arumugam wrote the initial draft of the manuscript that was edited by Tammy Kielian. Prabhakar Arumugam created the figures using BioRender.

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