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  • Basic Science Article
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Neonatal immune cells have heightened responses following in-utero exposure to chorioamnionitis or COVID-19

Pediatric Research (2023)Cite this article

Abstract

Background

Chorioamnionitis alters neonatal immune responses. Gestational COVID-19 infection is associated with adverse pregnancy outcomes, but its impact on neonatal immunity is unclear. We hypothesized that gestational COVID-19 exposure would result in exaggerated neonatal immune responses, similar to chorioamnionitis-exposed neonates.

Methods

Term umbilical cord blood mononuclear cells (CBMCs) were isolated from neonates exposed to chorioamnionitis, gestational COVID-19 or unexposed controls. CBMCs were cultured and stimulated with heat-killed Escherichia coli, Streptococcus agalactiae or Staphylococcus epidermidis. A multiplexed protein assay was used to measure cytokine levels in cell culture supernatants and flow cytometry was used to evaluate cellular-level cytokine expression.

Results

Both chorioamnionitis-exposed and COVID-19 exposed CBMCs demonstrated upregulation of IL-1β and IL-6 compared to unexposed CBMCs, while only COVID-19 exposure resulted in IL-8 upregulation. There were no differences between chorioamnionitis-exposed and COVID-19 exposed CBMCs when these groups were directly compared. Flow cytometry demonstrated immune cell subset specific differences in cytokine expression between the exposure groups.

Conclusion

The fetal/neonatal response to maternal inflammation differed based on immune cell subset and etiology of inflammation, but the global neonatal cytokine responses were similar between exposure groups. This suggests that targeting perinatal inflammation rather than the specific etiology may be a possible therapeutic approach.

Impact

  • Neonatal immune cells have similar pathogen-associated global cytokine responses, but different cell-level immune responses, following in-utero exposure to chorioamnionitis or COVID-19.

  • This is the first study to directly compare immune responses between neonates exposed to chorioamnionitis and COVID-19.

  • This suggests that the fetal/neonatal cellular response to perinatal inflammation differs based on the etiology and severity of maternal inflammation, but still results in a similar overall inflammatory profile regardless of the cause of perinatal inflammation.

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Fig. 1: Chorioamnionitis-exposed CBCMs have elevated IL-1β and IL-6 levels after heat-killed bacterial stimulation compared to unexposed CBMCs.
Fig. 2: COVID-19 exposed CBMCs demonstrate elevated IL-1β, IL-6, and IL-8 levels after heat-killed bacterial stimulation compared to unexposed CBMCs.
Fig. 3: There are no differences in cytokine profiles between chorioamnionitis and COVID-19 exposed CBMCs.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to acknowledge several people who contributed to the generation of data for this manuscript including: Shiloh Lueschow. This work was supported by the National Institutes of Health R01AI141673 (JB).

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Authors and Affiliations

  1. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, USA

    Annemarie Gilley

  2. Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Timothy J. Boly, Austin Paden & Jennifer Bermick

  3. Iowa Inflammation Program, University of Iowa, Iowa City, IA, USA

    Timothy J. Boly, Austin Paden & Jennifer Bermick

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Contributions

A.G.—methodology, data acquisition, formal analysis, investigation, writing-original draft. A.P.—methodology, data acquisition, writing-review and editing. T.J.B.—methodology, data acquisition, writing-review and editing. J.B.—conceptualization, methodology, validation, formal analysis, investigation, writing-review and editing, supervision, funding acquisition.

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Correspondence to Annemarie Gilley.

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Gilley, A., Boly, T.J., Paden, A. et al. Neonatal immune cells have heightened responses following in-utero exposure to chorioamnionitis or COVID-19. Pediatr Res (2023). https://doi.org/10.1038/s41390-023-02888-5

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