Immunometabolic approaches to prevent, detect, and treat neonatal sepsis

Abstract

The first days of postnatal life are energetically demanding as metabolic functions change dramatically to accommodate drastic environmental and physiologic transitions after birth. It is increasingly appreciated that metabolic pathways are not only crucial for nutrition but also play important roles in regulating inflammation and the host response to infection. Neonatal susceptibility to infection is increased due to a functionally distinct immune response characterized by high reliance on innate immune mechanisms. Interactions between metabolism and the immune response are increasingly recognized, as changes in metabolic pathways drive innate immune cell function and activation and consequently host response to pathogens. Moreover, metabolites, such as acetyl-coenzyme A (acetyl-CoA) and succinate have immunoregulatory properties and serve as cofactors for enzymes involved in epigenetic reprogramming or “training” of innate immune cells after an initial infectious exposure. Highly sensitive metabolomic approaches allow us to define alterations in metabolic signatures as they change during ontogeny and as perturbed by immunization or infection, thereby linking metabolic pathways to immune cell effector functions. Characterizing the ontogeny of immunometabolism will offer new opportunities to prevent, diagnose, and treat neonatal sepsis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1

References

  1. 1.

    Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).

  2. 2.

    GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018).

  3. 3.

    WHO. Child Mortality and Causes of Death. Global Health Observatory Data (WHO, 2017). https://www.who.int/gho/child_health/mortality/en/.

  4. 4.

    Srinivasjois, R. et al. Association of gestational age at birth with reasons for subsequent hospitalisation: 18 years of follow-up in a Western Australian Population Study. PLoS ONE 10, e0130535 (2015).

  5. 5.

    Wynn, J. L. Defining neonatal sepsis. Curr. Opin. Pediatr. 28, 135–140 (2016).

  6. 6.

    Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007).

  7. 7.

    Stiehm, E. R., Niehues, T. & Levy, O. Recognition of immunodeficiency in the first three months of life. UpToDate https://www.uptodate.com/ (2018).

  8. 8.

    Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

  9. 9.

    O’Neill, L. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16(Sep), 553–565 (2016).

  10. 10.

    Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562–2571 (2016).

  11. 11.

    Lee, A. H. et al. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory. Nat. Commun. 10, 1092 (2019).

  12. 12.

    Evangelatos, N. et al. Metabolomics in sepsis and its impact on public health. Public Health Genomics 20, 274–285 (2017).

  13. 13.

    Angus, D. C. & van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).

  14. 14.

    Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).

  15. 15.

    Cheng, S. C. et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406–413 (2016).

  16. 16.

    Ghazal, P., Dickinson, P. & Smith, C. L. Early life response to infection. Curr. Opin. Infect. Dis. 26, 213–218 (2013).

  17. 17.

    Wynn, J. L. et al. The influence of developmental age on the early transcriptomic response of children with septic shock. Mol. Med. 17, 1146–1156 (2011).

  18. 18.

    Kollmann, T. R. et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183, 7150–7160 (2009).

  19. 19.

    Shen, C. M. et al. Development of monocyte Toll-like receptor 2 and Toll-like receptor 4 in preterm newborns during the first few months of life. Pediatr. Res. 73, 685–691 (2013).

  20. 20.

    Marchant, E. A. et al. Attenuated innate immune defenses in very premature neonates during the neonatal period. Pediatr. Res. 78, 492–497 (2015).

  21. 21.

    Smith, C. L. et al. Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nat. Commun. 5, 4649 (2014).

  22. 22.

    Harbeson, D. et al. Energy demands of early life drive a disease tolerant phenotype and dictate outcome in neonatal bacterial sepsis. Front. Immunol. 9, 1918 (2018).

  23. 23.

    Kan, B. et al. Cellular metabolism constrains innate immune responses in early human ontogeny. Nat. Commun. 9, 4822 (2018).

  24. 24.

    Bours, M. J. et al. Adenosine 5’-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharm. Ther. 112, 358–404 (2006).

  25. 25.

    Idzko, M., Ferrari, D. & Eltzschig, H. K. Nucleotide signalling during inflammation. Nature 509, 310–317 (2014).

  26. 26.

    Yegutkin, G. G. Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochim. Biophys. Acta 1783, 673–694 (2008).

  27. 27.

    Ledderose, C. et al. Purinergic signaling and the immune response in sepsis: a review. Clin. Ther. 38, 1054–1065 (2016).

  28. 28.

    Pettengill, M. et al. Soluble ecto-5’-nucleotidase (5’-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J. Biol. Chem. 288, 27315–27326 (2013).

  29. 29.

    Levy, O. et al. The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J. Immunol. 177, 1956–1966 (2006).

  30. 30.

    Dreschers, S. et al. Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats. Nat. Commun. 10, 1685 (2019).

  31. 31.

    Weichhart, T., Hengstschlager, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15, 599–614 (2015).

  32. 32.

    Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014).

  33. 33.

    Ulas, T. et al. S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat. Immunol. 18, 622–632 (2017).

  34. 34.

    Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).

  35. 35.

    Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013).

  36. 36.

    Feingold, K. R. et al. Mechanisms of triglyceride accumulation in activated macrophages. J. Leukoc. Biol. 92, 829–839 (2012).

  37. 37.

    Moon, J.-S. et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat. Med. 22, 1002 (2016).

  38. 38.

    Innis, S. M. Essential fatty acids in growth and development. Prog. Lipid Res. 30, 39–103 (1991).

  39. 39.

    Varga, T., Czimmerer, Z. & Nagy, L. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim. Biophys. Acta 1812, 1007–1022 (2011).

  40. 40.

    Bouhlel, M. A. et al. PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137–143 (2007).

  41. 41.

    Ricote, M. et al. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

  42. 42.

    Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014).

  43. 43.

    Kelly, D. & Wischmeyer, P. E. Role of L-glutamine in critical illness: new insights. Curr. Opin. Clin. Nutr. Metab. Care 6, 217–222 (2003).

  44. 44.

    Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705 (2014).

  45. 45.

    Murphy, C. & Newsholme, P. Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production. Clin. Sci. (Lond.) 95, 397–407 (1998).

  46. 46.

    Wallace, C. & Keast, D. Glutamine and macrophage function. Metabolism 41, 1016–1020 (1992).

  47. 47.

    Sarafidis, K. et al. Urine metabolomics in neonates with late-onset sepsis in a case-control study. Sci. Rep. 7, 45506 (2017).

  48. 48.

    Badurdeen, S., Mulongo, M. & Berkley, J. A. Arginine depletion increases susceptibility to serious infections in preterm newborns. Pediatr. Res. 77, 290 (2014).

  49. 49.

    Gerdes, J. S. Diagnosis and management of bacterial infections in the neonate. Pediatr. Clin. North Am. 51, 939–959 (2004).

  50. 50.

    Benitz, W. E. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin. Perinatol. 37, 421–438 (2010).

  51. 51.

    Hornik, C. P. et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum. Dev. 88(Suppl 2), S69–S74 (2012).

  52. 52.

    Skibsted, S. et al. Bench-to-bedside review: future novel diagnostics for sepsis - a systems biology approach. Crit. Care 17, 231 (2013).

  53. 53.

    Johnson, C. H., Ivanisevic, J. & Siuzdak, G. Metabolomics: beyond biomarkers and towards mechanisms. Nat. Rev. Mol. Cell Biol. 17, 451–459 (2016).

  54. 54.

    Vuckovic, D. & Pawliszyn, J. Systematic evaluation of solid-phase microextraction coatings for untargeted metabolomic profiling of biological fluids by liquid chromatography-mass spectrometry. Anal. Chem. 83, 1944–1954 (2011).

  55. 55.

    OuYang, D. et al. Metabolomic profiling of serum from human pancreatic cancer patients using 1H NMR spectroscopy and principal component analysis. Appl. Biochem. Biotechnol. 165, 148–154 (2011).

  56. 56.

    Xuan, J. et al. Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J. Proteome Res. 10, 5433–5443 (2011).

  57. 57.

    Hasokawa, M. et al. Identification of biomarkers of stent restenosis with serum metabolomic profiling using gas chromatography/mass spectrometry. Circ. J. 76, 1864–1873 (2012).

  58. 58.

    Alvarez-Sanchez, B., Priego-Capote, F. & Luque de Castro, M. D. Study of sample preparation for metabolomic profiling of human saliva by liquid chromatography-time of flight/mass spectrometry. J. Chromatogr. A 1248, 178–181 (2012).

  59. 59.

    Montuschi, P. et al. NMR spectroscopy metabolomic profiling of exhaled breath condensate in patients with stable and unstable cystic fibrosis. Thorax 67, 222–228 (2012).

  60. 60.

    Carraro, S. et al. Metabolomics applied to exhaled breath condensate in childhood asthma. Am. J. Respir. Crit. Care Med. 175, 986–990 (2007).

  61. 61.

    Chow, J. et al. Fecal metabolomics of healthy breast-fed versus formula-fed infants before and during in vitro batch culture fermentation. J. Proteome Res. 13, 2534–2542 (2014).

  62. 62.

    Goedert, J. J. et al. Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis 35, 2089–2096 (2014).

  63. 63.

    Fanos, V. et al. Urinary (1)H-NMR and GC-MS metabolomics predicts early and late onset neonatal sepsis. Early Hum. Dev. 90(Suppl 1), S78–S83 (2014).

  64. 64.

    Stringer, K. A. et al. Metabolic consequences of sepsis-induced acute lung injury revealed by plasma (1)H-nuclear magnetic resonance quantitative metabolomics and computational analysis. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L4–L11 (2011).

  65. 65.

    Cambiaghi, A. et al. Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. Sci. Rep. 7, 9748 (2017).

  66. 66.

    Langley, R. J. et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci. Transl. Med. 5, 195ra95 (2013).

  67. 67.

    Netea, M. G. & van der Meer, J. W. Trained immunity: an ancient way of remembering. Cell Host Microbe 21, 297–300 (2017).

  68. 68.

    Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

  69. 69.

    Bekkering, S. et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135.e9–146.e9 (2018).

  70. 70.

    Benit, P. et al. Unsuspected task for an old team: succinate, fumarate and other Krebs cycle acids in metabolic remodeling. Biochim. Biophys. Acta 1837, 1330–1337 (2014).

  71. 71.

    Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

  72. 72.

    Liu, T. F. et al. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J. Biol. Chem. 287, 25758–25769 (2012).

  73. 73.

    Levy, O. & Wynn, J. L. A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105, 136–141 (2014).

  74. 74.

    Cernada, M. et al. Sepsis in preterm infants causes alterations in mucosal gene expression and microbiota profiles compared to non-septic twins. Sci. Rep. 6, 25497 (2016).

  75. 75.

    Stewart, C. et al. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr. 101, 1121–1127 (2012).

  76. 76.

    Gritz, E. C. & Bhandari, V. The human neonatal gut microbiome: a brief review. Front. Pediatr. 3, 17 (2015).

  77. 77.

    Gibson, M. K. et al. Developmental dynamics of the preterm infant gut microbiota and antibiotic resistome. Nat. Microbiol. 1, 16024 (2016).

  78. 78.

    Jiang, P. et al. Antibiotic treatment preventing necrotising enterocolitis alters urinary and plasma metabolomes in preterm pigs. J. Proteome Res. 16, 3547–3557 (2017).

  79. 79.

    Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

  80. 80.

    Vinolo, M. A. et al. Suppressive effect of short-chain fatty acids on production of proinflammatory mediators by neutrophils. J. Nutr. Biochem. 22, 849–855 (2011).

  81. 81.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

  82. 82.

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

  83. 83.

    Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).

  84. 84.

    Haak, B. W. & Wiersinga, W. J. The role of the gut microbiota in sepsis. Lancet Gastroenterol. Hepatol. 2, 135–143 (2017).

  85. 85.

    Black, R. E. et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 371, 243–260 (2008).

  86. 86.

    Walsh, V. & McGuire, W. Immunonutrition for preterm infants. Neonatology 115, 398–405 (2019).

  87. 87.

    Freitas, B. A. et al. Nutritional therapy and neonatal sepsis. Rev. Bras. Ter. Intensiv. 23, 492–498 (2011).

  88. 88.

    Dhandai, R. et al. Association of vitamin D deficiency with an increased risk of late-onset neonatal sepsis. Paediatr. Int. Child Health 38, 193–197 (2018).

  89. 89.

    Parekh, D. et al. Vitamin D deficiency in human and murine sepsis. Crit. Care Med. 45, 282–289 (2017).

  90. 90.

    Onwuneme, C. et al. Vitamin D enhances reactive oxygen intermediates production in phagocytic cells in term and preterm infants. Pediatr. Res. 79, 654–661 (2016).

  91. 91.

    Schlesinger, L. & Uauy, R. Nutrition and neonatal immune function. Semin. Perinatol. 15, 469–477 (1991).

  92. 92.

    Loui, A. et al. Nutritional zinc balance in extremely low-birth-weight infants. J. Pediatr. Gastroenterol. Nutr. 32, 438–442 (2001).

  93. 93.

    Besecker, B. Y. et al. A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am. J. Clin. Nutr. 93, 1356–1364 (2011).

  94. 94.

    Cvijanovich, N. Z. et al. Zinc homeostasis in pediatric critical illness. Pediatr. Crit. Care Med. 10, 29–34 (2009).

  95. 95.

    Nowak, J. E. et al. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. Pediatr. Crit. Care Med. 13, e323–e329 (2012).

  96. 96.

    Alker, W. & Haase, H. Zinc and sepsis. Nutrients 10, 976 (2018).

  97. 97.

    Terrin, G. et al. Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: a hospital-based randomized, placebo-controlled trial in an industrialized country. Am. J. Clin. Nutr. 98, 1468–1474 (2013).

  98. 98.

    Tang, Z. et al. Efficacy of zinc supplementation for neonatal sepsis: a systematic review and meta-analysis. J. Matern. Fetal Neonatal Med. 32, 1213–1218 (2019).

  99. 99.

    Darlow, B. A. & Austin, N. C. Selenium supplementation to prevent short-term morbidity in preterm neonates. Cochrane Database Syst. Rev. CD003312 (2003).

  100. 100.

    Aggarwal, R. et al. Selenium supplementation for prevention of late-onset sepsis in very low birth weight preterm neonates. J. Trop. Pediatr. 62, 185–193 (2016).

  101. 101.

    Gitto, E. et al. Effects of melatonin treatment in septic newborns. Pediatr. Res. 50, 756–760 (2001).

  102. 102.

    Gitto, E. et al. Protective role of melatonin in neonatal diseases. Oxid. Med. Cell Longev. 2013, 980374 (2013).

  103. 103.

    Nakamoto, N. et al. A free radical scavenger, edaravone, attenuates steatosis and cell death via reducing inflammatory cytokine production in rat acute liver injury. Free Radic. Res. 37, 849–859 (2003).

  104. 104.

    Kato, S. et al. Edaravone, a novel free radical scavenger, reduces high-mobility group box 1 and prolongs survival in a neonatal sepsis model. Shock 32, 586–592 (2009).

  105. 105.

    Speer, E. M. et al. Pentoxifylline alone or in combination with gentamicin or vancomycin inhibits live microbe-induced proinflammatory cytokine production in human cord blood and cord blood monocytes in vitro. Antimicrob. Agents Chemother. 62, e01462 (2018).

  106. 106.

    Schuller, S. S. et al. Pentoxifylline modulates LPS-induced hyperinflammation in monocytes of preterm infants in vitro. Pediatr. Res. 82, 215–225 (2017).

  107. 107.

    Pammi, M. & Haque, K. N. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst. Rev. CD004205 (2015).

  108. 108.

    Shabaan, A. E. et al. Pentoxifylline therapy for late-onset sepsis in preterm infants: a randomized controlled trial. Pediatr. Infect. Dis. J. 34, e143–e148 (2015).

Download references

Acknowledgements

We thank Precision Vaccines Program graphic artist Kristin Johnson for optimizing the figure and Precision Vaccines Program Coordinator, Ms. Diana Vo, for important administrative support.

Author information

M.G.C.: conception and design, drafting the article; A.A.: substantial contributions to conception and design, drafting the article, revising the article critically for important intellectual content; J.D.-A.: revising the article critically for important intellectual content; K.S.: revising the article critically for important intellectual content; J.L.-S.: drafting the article and revising it critically for important intellectual content; M.D.C. and O.L.: revising the article critically for important intellectual content, final approval of the version to be published.

Correspondence to Ofer Levy.

Ethics declarations

Competing interests

O.L. is a named inventor on several patents relating to vaccine adjuvants.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Conti, M.G., Angelidou, A., Diray-Arce, J. et al. Immunometabolic approaches to prevent, detect, and treat neonatal sepsis. Pediatr Res 87, 399–405 (2020). https://doi.org/10.1038/s41390-019-0647-6

Download citation