Abstract
Background
Preterm infants are at high risk of infection and have distinct pathogen recognition responses. Suggested mechanisms include soluble mediators that enhance cellular levels of cAMP. The aim of this study was to assess the relationship between blood cAMP concentrations and TLR-mediated cytokine production in infants during the first month of life.
Methods
Cord and serial peripheral blood samples (days of life 1–28) were obtained from a cohort of very preterm (<30 weeks’ gestational age) and term human infants. Whole-blood concentrations of cAMP and FSL-1 and LPS in vitro stimulated cytokine concentrations were measured by ELISA and multiplex bead assay.
Results
cAMP concentrations were higher in cord than in peripheral blood, higher in cord blood of female preterm infants, and lower at Days 1 and 7 in infants exposed to chorioamnionitis, even after adjusting for leukocyte counts. TLR2 and TLR4-mediated TNF-α, IL-1β, IL-6, IL-12p70, and IL-10 production in vitro increased over the first month of life in preterm infants and were positively correlated with leukocyte-adjusted cAMP levels and reduced by exposure to chorioamnionitis.
Conclusions
The ontogeny of blood cAMP concentrations and associations with chorioamnionitis and TLR-mediated production of cytokines suggest that this secondary messenger helps shape distinct neonatal pathogen responses in early life.
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Acknowledgements
This project was supported by a National Health & Medical Research Council (NHMRC) of Australia project grant award (572548). S.S.S. was supported by a Max-Kade fellowship. D.B. is supported by an NHMRC Senior Research Fellowship (1046518). Research at the Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Program. Work in O.L.’s laboratory was supported by U.S. National Institutes of Health (NIH) National Institutes of Allergy and Infectious Diseases (NIAID) grants 1RO1AI00135-01, Human Immunology Project Consortium (HIPC) award 1U19AI118608-01A1 and U01AI12484-01, as well as Global Health (OPPGH5284) and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation. The Precision Vaccines Program is supported by an internal award from the Boston Children’s Hospital Department of Pediatrics.
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T.S., S.D.v.H., M.P., D.B., O.L., A.J.C. made substantial contributions to conception and design. T.S., S.D.v.H., J.H., M.P., A.J.C. made substantial contributions to data acquisition and analysis. All authors made contributions to interpretation of data and drafting/revising critically for important intellectual content. All authors approve the version to be published.
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Over the past 5 years, O.L.’s laboratory has received sponsored research support from MedImmune and Crucell (Johnson & Johnson) and reagent support from the Infectious Diseases Research Institute. The other authors declare no competing interests.
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Strunk, T., van Haren, S.D., Hibbert, J. et al. Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro. Pediatr Res 88, 717–725 (2020). https://doi.org/10.1038/s41390-019-0586-2
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DOI: https://doi.org/10.1038/s41390-019-0586-2
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