Skip to main content
SpringerLink
Log in

Identification of generic and pathogen-specific cord blood monocyte transcriptomes reveals a largely conserved response in preterm and term newborn infants

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to “immature” innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37–40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-κB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis.

Key messages

  • E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes.

  • The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling.

  • IFN-genes are differentially regulated by E. coli and S. epidermidis in monocytes.

  • These responses are largely unaffected by GA or exposure to chorioamnionitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692

    Article  CAS  PubMed  Google Scholar 

  2. de Jong E, Strunk T, Burgner D, Lavoie PM, Currie A (2017) The phenotype and function of preterm infant monocytes: implications for susceptibility to infection. Journal of Leukocyte Biology. https://doi.org/10.1189/jlb.4RU0317-111R

  3. Strunk T, Richmond P, Prosser A, Simmer K, Levy O, Burgner D, Currie A (2011) Method of bacterial killing differentially affects the human innate immune response to Staphylococcus epidermidis. Innate Immun 17:508–516

    Article  CAS  PubMed  Google Scholar 

  4. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP, Bizzarro MJ, Goldberg RN, Frantz ID, 3rd, Hale EC et al (2011) Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics 127: 817–826

  5. Dong Y, Speer CP (2015) Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed 100:F257–F263

    Article  PubMed  Google Scholar 

  6. Moine P, Abraham E (2004) Immunomodulation and sepsis: impact of the pathogen. Shock 22:297–308

    Article  CAS  PubMed  Google Scholar 

  7. Oblak A, Jerala R (2015) The molecular mechanism of species-specific recognition of lipopolysaccharides by the MD-2/TLR4 receptor complex. Mol Immunol 63:134–142

    Article  CAS  PubMed  Google Scholar 

  8. Bi D, Qiao L, Bergelson I, Ek CJ, Duan L, Zhang X, Albertsson A-M, Pettengill M, Kronforst K, Ninkovic J et al (2015) Staphylococcus epidermidis bacteremia induces brain injury in neonatal mice via toll-like receptor 2-dependent and -independent pathways. J Infect Dis. https://doi.org/10.1093/infdis/jiv231

  9. van der Poll T, Opal SM (2008) Host–pathogen interactions in sepsis. Lancet Infect Dis 8:32–43

    Article  PubMed  Google Scholar 

  10. Tang BMP, McLean AS, Dawes IW, Huang SJ, Cowley MJ, Lin RCY (2008) Gene-expression profiling of Gram-positive and Gram-negative sepsis in critically ill patients. Crit Care Med 36:1125–1128

    Article  CAS  PubMed  Google Scholar 

  11. Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R, Charles A, Burgner D (2012) Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 129:e134–e141

    Article  PubMed  Google Scholar 

  12. Goldenberg RL, Hauth JC, Andrews WW (2000) Intrauterine infection and preterm delivery. New Engl J Med 342:1500–1507

    Article  CAS  PubMed  Google Scholar 

  13. Macaubas S, Burton T, Yabuhara H, Smallacombe K, Jenmalm H (1999) Regulation of T-helper cell responses to inhalant allergen during early childhood. Clin Exp Allergy 29:1223–1231

    Article  CAS  PubMed  Google Scholar 

  14. Kirkham LA, Corscadden KJ, Wiertsema SP, Currie AJ, Richmond PC (2013) A practical method for preparation of pneumococcal and nontypeable Haemophilus influenzae inocula that preserves viability and immunostimulatory activity. BMC Res Notes 6:522

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wisgrill L, Groschopf A, Herndl E, Sadeghi K, Spittler A, Berger A, Förster-Waldl E (2016) Reduced TNF-α response in preterm neonates is associated with impaired nonclassic monocyte function. J Leukoc Biol 100:607–612

    Article  CAS  PubMed  Google Scholar 

  16. Liao Y, Smyth GK, Shi W (2013) The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res 41:e108

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930

    Article  CAS  PubMed  Google Scholar 

  18. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. https://doi.org/10.1093/nar/gkv007

  19. Law CW, Chen Y, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15: R29

  20. Robinson MD, Oshlack A (2010) A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol 11:R25

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wu D, Lim E, Vaillant F, Asselin-Labat M-L, Visvader JE, Smyth GK (2010) ROAST: rotation gene set tests for complex microarray experiments. Bioinformatics 26:2176–2182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. de Jager W, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT (2003) Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 10:133–139

    PubMed  PubMed Central  Google Scholar 

  23. Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol 14:546–558

    Article  CAS  PubMed  Google Scholar 

  24. Martin M, Schifferle RE, Cuesta N, Vogel SN, Katz J, Michalek SM (2003) Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J Immunol 171:717–725

    Article  CAS  PubMed  Google Scholar 

  25. Dickinson P, Smith CL, Forster T, Craigon M, Ross AJ, Khondoker MR, Ivens A, Lynn DJ, Orme J, Jackson A et al (2015) Whole blood gene expression profiling of neonates with confirmed bacterial sepsis. Genomics Data 3:41–48

    Article  PubMed  Google Scholar 

  26. Smith CL, Dickinson P, Forster T, Craigon M, Ross A, Khondoker MR, France R, Ivens A, Lynn DJ, Orme J et al (2014) Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nat Commun 5:4649

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wynn JL, Guthrie SO, Wong HR, Lahni P, Ungaro R, Lopez MC, Baker HV, Moldawer LL (2015) Postnatal age is a critical determinant of the neonatal host response to sepsis. Mol Med 21:496–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nau GJ, Richmond JFL, Schlesinger A, Jennings EG, Lander ES, Young RA (2002) Human macrophage activation programs induced by bacterial pathogens. Proc Natl Acad Sci U S A 99:1503–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Garofoli F, Borghesi A, Mazzucchelli I, Tzialla C, Di Comite A, Tinelli C, Manzoni P, Stronati M (2010) Preterm newborns are provided with triggering receptor expressed on myeloid cells-1. Int J Immunopathol Pharmacol 23: 1297–1301

  30. Arts RJW, Joosten LAB, van der Meer JWM, Netea MG (2013) TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol 93:209–215

    Article  CAS  PubMed  Google Scholar 

  31. Bouchon A, Facchetti F, Weigand MA, Colonna M (2001) TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410:1103–1107

    Article  CAS  PubMed  Google Scholar 

  32. Qian L, Weng X-W, Chen W, Sun C-H, Wu J (2014) TREM-1 as a potential therapeutic target in neonatal sepsis. Int J Clin Exp Med 7:1650–1658

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Saldir M, Tunc T, Cekmez F, Cetinkaya M, Kalayci T, Fidanci K, Babacan O, Erdem G, Kocak N, Sari E (2015) Endocan and soluble triggering receptor expressed on myeloid cells-1 as novel markers for neonatal sepsis. Pediatrics & Neonatology

  34. Arízaga-Ballesteros V, Alcorta-García MR, Lázaro-Martínez LC, Amézquita-Gómez JM, Alanís-Cajero JM, Villela L, Castorena-Torres F, Lara-Díaz VJ (2015) Can sTREM-1 predict septic shock & death in late-onset neonatal sepsis? A pilot study. Int J Infect Dis 30:27–32

    Article  PubMed  Google Scholar 

  35. Lu Y-C, Yeh W-C, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42:145–151

    Article  CAS  PubMed  Google Scholar 

  36. Doyle SE, Vaidya SA, O'Connell R, Dadgostar H, Dempsey PW, T-T W, Rao G, Sun R, Haberland ME, Modlin RL et al (2002) IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17:251–263

    Article  CAS  PubMed  Google Scholar 

  37. Kovarik P, Castiglia V, Ivin M, Ebner F (2016) Type I interferons in bacterial infections: a balancing act. Front Immunol 7:652

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ulas T, Pirr S, Fehlhaber B, Bickes MS, Loof TG, Vogl T, Mellinger L, Heinemann AS, Burgmann J, Schoning J et al (2017) S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat Immunol 18:622–632

    Article  CAS  PubMed  Google Scholar 

  39. Härtel C, Osthues I, Rupp J, Haase B, Röder K, Göpel W, Herting E, Schultz C (2008) Characterisation of the host inflammatory response to Staphylococcus epidermidis in neonatal whole blood. Arch Dis Child Fetal Neonatal Ed 93:F140–F145

    Article  PubMed  Google Scholar 

  40. Sadeghi K, Berger A, Langgartner M, Prusa AR, Hayde M, Herkner K, Pollak A, Spittler A, Forster-Waldl E (2007) Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J Infect Dis 195:296–302

    Article  CAS  PubMed  Google Scholar 

  41. Strunk T, Prosser A, Levy O, Philbin V, Simmer K, Doherty D, Charles A, Richmond P, Burgner D, Currie A (2012) Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation. Pediatr Res 72:10–18

    Article  CAS  PubMed  Google Scholar 

  42. Marchant EA, Kan B, Sharma AA, van Zanten A, Kollmann TR, Brant R, Lavoie PM (2015) Attenuated innate immune defenses in very premature neonates during the neonatal period. Pediatr Res. https://doi.org/10.1038/pr.2015.132

  43. Sharma AA, Jen R, Brant R, Ladd M, Huang Q, Skoll A, Senger C, Turvey SE, Marr N, Lavoie PM (2014) Hierarchical maturation of innate immune defences in very preterm neonates. Neonatology 106:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lissner MM, Thomas BJ, Wee K, Tong A-J, Kollmann TR, Smale ST (2015) Age-related gene expression differences in monocytes from human neonates, young adults, and older adults. PLoS One 10:e0132061

    Article  PubMed  PubMed Central  Google Scholar 

  45. Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR (2006) The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 177:1956–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Meijerink M, Ulluwishewa D, Anderson RC, Wells JM (2011) Cryopreservation of monocytes or differentiated immature DCs leads to an altered cytokine response to TLR agonists and microbial stimulation. J Immunol Methods 373:136–142

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This project was kindly supported by funding from the National Health & Medical Research Council of Australia, the Princess Margaret Hospital Foundation, and the BrightSpark Foundation.

Author information

Authors and Affiliations

  1. Medical & Molecular Sciences, School of Veterinary & Life Sciences, Murdoch University, South Street, Murdoch, Western Australia, 6150, Australia

    Emma de Jong & Andrew J. Currie

  2. School of Medicine, Flinders University, Adelaide, Australia

    David G. Hancock

  3. Centre for Neonatal Research & Education and Division of Paediatrics, University of Western Australia, Perth, Australia

    Julie Hibbert, Peter Richmond, Karen Simmer, Tobias Strunk & Andrew J. Currie

  4. Centre for Stem Cell Systems, Department of Anatomy and Neuroscience, MDHS, University of Melbourne, Melbourne, Australia

    Christine Wells

  5. The Walter and Eliza Hall Institute, Melbourne, Australia

    Christine Wells

  6. Royal Children’s Hospital, Murdoch Children’s Research Institute, Melbourne, Australia

    David Burgner

  7. Department of Paediatrics, University of Melbourne, Melbourne, Australia

    David Burgner

  8. Department of Paediatrics, Monash University, Melbourne, Australia

    David Burgner

  9. Neonatal Directorate, King Edward Memorial and Princess Margaret Hospitals, Subiaco, Australia

    Tobias Strunk

Authors
  1. Emma de Jong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David G. Hancock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Hibbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Richmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen Simmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Burgner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tobias Strunk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew J. Currie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emma de Jong.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Electronic supplementary material

ESM 1

(PDF 737 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Jong, E., Hancock, D.G., Hibbert, J. et al. Identification of generic and pathogen-specific cord blood monocyte transcriptomes reveals a largely conserved response in preterm and term newborn infants. J Mol Med 96, 147–157 (2018). https://doi.org/10.1007/s00109-017-1609-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-017-1609-2

Keywords

Search

Navigation