Biology subjects

Klabunde, B.

Publications and source records attributed to Klabunde, B..

8 recordsLinked to original sources

bioRxiv2026

NAD metabolism mediates a sex-specific protection against early life infections

Sex influences early-life immunity and infection outcomes, yet how metabolic mechanisms regulate these effects remain unclear. As nicotinamide adenine dinucleotide (NAD) can support mitochondrial metabolism and immune function, here we explore how NAD metabolism contributes to sex-specific protection against infections in early life. First, in two independent cohorts of 700 and 386 children, we found that females at birth had higher blood NAD levels than males, and strikingly higher birth NAD levels were associated with reduced infection burdens during the first 3 years of life in females, but with tendency of increased burdens in males. At 18 months, plasma nicotinamide associated with sex-specific cytokine responses to antigen challenges and showed a stronger positive association with tricarboxylic acid cycle (TCA) activity in females. Next, we verified the causal effects of NAD metabolism on infection protection by testing the supplementation of NAD precursor nicotinamide riboside (NR) in infected newborn piglets, used as a translational model of infection-sensitive infants. NR treatment improved survival, bacterial clearance, and disease tolerance only in females, but not in males. Mechanistically, NR increased levels of hepatic TCA cycle metabolites fumarate and malate, and enhanced hepatic inflammatory, hormonal, and mitochondrial-associated transcriptional programs, again only in females. Finally, the sex-specific immune functions mediated by NR were also validated in blood and immune cells in vitro. Collectively, we identified NAD metabolism as a sex-dependent immunometabolic mediator in early-life infection. Our findings suggest the potential of sex-stratified nutritional interventions in infection-sensitive infants.

immunology↗

bioRxiv2026

Glucose restriction reduces systemic, but not cardiac, inflammation during neonatal sepsis in preterm pigs

Introduction: Preterm infants are highly susceptible to sepsis and hyperglycemia may exacerbate inflammation and worsen outcomes. We examined how glucose provision influences systemic and cardiac responses during neonatal sepsis in preterm pigs. Methods: Preterm piglets (90 % gestation) were infused with Staphylococcus epidermidis to induce sepsis. In Experiment 1, three ventilated and anesthetized piglets were continuously monitored for mean arterial pressure (MAP) and blood gases to characterize acute cardiovascular and metabolic deterioration. In Experiment 2, thirty-three piglets were randomized to standard (14 g/kg/day) or reduced (3.5 g/kg/day) glucose provision, with or without infection, and followed for 20h. Results: Infection in Experiment 1 caused progressive hypotension, acidosis, and hypoxia, mirroring clinical neonatal sepsis. In Experiment 2, reduced glucose provision improved survival (77 % vs 46 %, p = 0.06) and attenuated systemic inflammation, with lower IL-6 and higher IL-10 concentrations. Infection induced mild cardiac neutrophil infiltration, without affecting plasma troponin T but clearly reduced cardiomyocyte mitotic density and triggered upregulation of inflammatory transcriptional pathways (NF-{kappa}B, JAK-STAT) and suppression of oxidative phosphorylation. In infected animals. glucose restriction preserved cardiomyocyte mitotic density but did not alter cardiac structure, injury markers or gene expression. Conclusion: Neonatal infection induced circulatory failure, suppression of cardiomyocyte proliferation and upregulation of inflammatory genes in cardiac tissue, while reduced glucose provision mitigated systemic immune responses and preserved cardiomyocyte proliferation.

immunology↗

bioRxiv2026

Reduced parenteral glucose supply in preterm neonatal infection ameliorates the pulmonary damage

Preterm infants are acutely susceptible to neonatal sepsis, a syndrome characterized by systemic pro-inflammatory activity and life-threatening multi-organ dysfunction. However, the specific pulmonary pathological response to sepsis and the potential for metabolic interventions to mitigate lung injury remain poorly characterized. Herein, we evaluated the impact of varying parenteral glucose regimens on pulmonary outcomes during severe infection using a preterm piglet model. Genome-wide gene expression analysis was used to characterize lung transcriptome profiles. The relationships between gene expression and circulating biochemical and immune profiles were also investigated. Our findings demonstrate that significant pulmonary tissue damage is a hallmark of neonatal sepsis. A reduced-glucose regimen markedly attenuated pulmonary tissue damage while simultaneously alleviating systemic metabolic acidosis and hyperlactatemia. Mechanistically, lung transcriptome profiling revealed a profound activation of pathways associated with inflammatory signaling, programmed cell death, and the dysregulation of glucose, amino acid, and lipid metabolism. The low-glucose intervention effectively mitigated these widespread molecular and metabolic disturbances, suggesting a restorative effect on the pulmonary transcriptome landscape. To facilitate further mechanistic exploration and the identification of novel therapeutic targets, we developed the NeoSepPulmoExplorer (https://pharmaco-omicslab.shinyapps.io/NeoSepPulmoExplorer/), an interactive web-based toolkit for better mechanistic understanding and the identification of potential treatment targets. These results collectively underscore the importance of metabolic modulation in preserving organ function, though further translational studies are requisite to improve clinical outcomes in septic neonates.

immunology↗

bioRxiv2025

Ketone and glycolytic metabolism are key modulators of inflammation during neonatal sepsis

Neonatal sepsis is a life-threatening condition in preterm infants, primarily due to a dysregulated immunometabolic response to infection. Sepsis and infection mortality are associated with excessive glycolysis-induced inflammation, impaired mitochondrial oxidative phosphorylation (OXPHOS) and loss of disease tolerance. Reduced glucose intake can reverse these dysregulations, but it is unclear how the mechanistic control of glycolysis-OXPHOS balance drives defense strategies and infection outcomes. Here, in a preterm piglet model of neonatal sepsis, glycolysis inhibition with 2-deoxyglucose (2-DG) completely prevents acute infection mortality, reduces systemic inflammation and markers of liver injury, accompanied by enhanced mitochondrial metabolism and disease tolerance. Strikingly, this protection by 2-DG is conferred despite elevated blood glucose levels and higher bacterial burdens than the infected controls. Alternatively, partial replacement of glucose intake with the ketone beta-hydroxybutyrate (BHB) abolishes sepsis-related mortality via improving disease tolerance and clinical parameters. This intervention also shifts the hepatic transcriptome away from inflammatory signaling and towards mitochondrial metabolism. In macrophages in vitro, BHB also exerts anti-inflammatory effects independently of metabolic modulation via the HCAR2 receptor. Finally, data from a cohort of 700 infants confirm an association of plasma BHB levels and anti-inflammatory state. These findings demonstrate that metabolic reprogramming through glycolysis inhibition or ketone supplementation is a promising therapeutic strategy to enhance disease tolerance and improve sepsis outcomes in neonates.

immunology↗

bioRxiv2025

Harnessing systemic glycolysis-TCA cycle axis to boost the host defense against newborn infection

Energy metabolism and immune response are tightly connected, but it is poorly understood how this interplay is regulated in early life to dictate host defense strategy, infection risks and severity. This interplay is particularly relevant for preterm, low birthweight or otherwise immunocompromised infants, who have poor metabolic control and increased risks of sepsis. Here, we utilized data from the COPSAC2010 cohort with 700 mother-child pairs and showed that plasma levels of TCA cycle metabolites in early life were associated with reduced childhood risk of bacterial infection and an attenuated systemic inflammatory response. Next, we explored how two distinct nutritional strategies, which were aimed at boosting TCA cycle activity instead of glycolysis, impacted neonatal host defense against a serious bloodstream infection in preterm piglets. Substituting galactose for glucose in parenteral nutrition enhanced disease tolerance in early phase of infection and overall glucose homeostasis, improving survival. Further, combining glucose restriction with supplementation of glucogenic amino acids conferred glycemic control and completely prevented sepsis and abnormal changes of organ injury markers. Mechanistically, this intervention enhanced both disease resistance and tolerance, accompanied by metabolic rewiring from glycolysis towards gluconeogenesis, TCA cycle activity and oxidative phosphorylation. Thus, optimized nutritional strategies controlling the interplay of energy metabolism and host defense may be lifesaving for infected infants. In briefNewborns rely on two distinct defense strategies to combat infections in early life. Disease resistance, fueled by aerobic glycolysis, seeks to actively eliminate microorganisms while disease tolerance, fueled by mitochondrial oxidative phosphorylation, seeks to reduce collateral tissue damage during infections. We found that in healthy human newborns, increased plasma levels of metabolites from the tricarboxylic acid (TCA) cycle were associated with lower burden of childhood infections and reduced pro-inflammatory status. In a newborn animal model of bloodstream infection, nutritional strategies boosting systemic TCA cycle activity, while reducing aerobic glycolysis, enhanced both host disease tolerance and resistance, thereby improving survival. These findings could pave a path for improved infection management in human newborns. HighlightsO_LIIn healthy children, higher plasma levels of TCA cycle metabolites are associated with lower infection risks and systemic inflammation. C_LIO_LIIn a neonatal infection model, the supply of galactose, instead of glucose, improves host glucose homeostasis and TCA cycle activity, improving disease tolerance and survival. C_LIO_LIA combination of glucose restriction and glucogenic amino acid supply also improves TCA cycle activity, enhancing both disease resistance and tolerance and completely preventing lethal sepsis. C_LI

immunology↗

bioRxiv2024

Regulation of defense strategies and host metabolism to survive neonatal infection

Two distinct defense strategies, resistance and tolerance, enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on tolerance to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to resistance that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between tolerance and resistance in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non- survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Relative to non-survivors, survivors displayed elevated resistance during the early phase of infection, followed by stronger tolerance in later stages. Conversely, animals succumbing to sepsis showed clear signs of respiratory and metabolic acidosis, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the tolerance phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics supported the finding of enhanced mitochondrial metabolism in survivors. Our findings suggest a link between mitochondrial metabolism, disease tolerance, and ultimately improved survival during infections in newborns. Metabolic regulations related to tolerance may be exploited to discover novel therapeutics for neonatal infection. Conflict-of-interest statementThe authors have declared that no conflict of interest exists.

immunology↗

bioRxiv2023

NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections

1.Lower respiratory tract infections caused by StreptococcusOpneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial cascade in Spn infections, predicting a novel antibacterial mechanism of NAD+.

immunology↗

bioRxiv2022

Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides

Bioactive peptides are key molecules in health and medicine. Deep learning holds a big promise for the discovery and design of bioactive peptides. Yet, suitable experimental approaches are required to validate candidates in high throughput and at low cost. Here, we established a cell- free protein synthesis (CFPS) pipeline for the rapid and inexpensive production of antimicrobial peptides (AMPs) directly from DNA templates. To validate our platform, we used deep learning to design thousands of AMPs de novo. Using computational methods, we prioritized 500 candidates that we produced and screened with our CFPS pipeline. We identified 30 functional AMPs, which we characterized further through molecular dynamics simulations, antimicrobial activity and toxicity. Notably, six de novo-AMPs feature broad-spectrum activity against multidrug-resistant pathogens and do not develop bacterial resistance. Our work demonstrates the potential of CFPS for production and testing of bioactive peptides within less than 24 hours and <10$ per screen.

synthetic biology↗