Innate immunity

Poster

Cellular Metabolic and Translational Constraints in Preterm Monocytes

Wednesday, June 14
6:15 PM - 7:45 PM

Human innate immune responses are broadly attenuated below 32 weeks of gestation, resulting in increased infections in infants born prematurely. However, despite decades of functional characterization of these cells, the underlying mechanism(s) remain unclear. A switch in energy metabolism, from oxidative phosphorylation to aerobic glycolysis, is required to increase protein synthesis during immune activation. Here, we performed a genome-wide transcriptomic analysis (Illumina HT-12 Human Bead Array) of LPS-stimulated (5h) genes comparing preterm, term (cord) and adult (peripheral) blood monocytes. We found comparable cytokine/chemokine gene responses across all three age groups, despite a lack of corresponding protein expression. In contrast, genes encoding ribosomal subunit were down-regulated in preterm monocytes. On that basis, we hypothesized that the lack of strong immune responses in preterm neonatal monocytes is due to a decreased glycolytic capacity. Using radioactive Met/Cys pulse-labeling, we confirm that blocking glycolysis impaired the increase in translation in primary human monocytes, after LPS stimulation. Accordingly, the glycolytic activity of preterm mononuclear cells was impaired relative to their adult and term counterparts, as shown by reduced lactate production (post-LPS) and reduced rate of extracellular acidification upon adding glucose (Agilent Seahorse Analyzer). Our preliminary data suggests that translation is substantially reduced in preterm monocytes, and that this mechanism is mTOR-related as evidence by lack of mTOR phosphorylation in preterm monocytes. Polysome profiling/qPCR experiments are underway to determine how selective this impairment in translation is. Altogether, our data provide a novel mechanism through which immune activation is constrained during fetal life.

Christina Michalski

University of British Columbia

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    Bernard Kan

    University of British Columbia

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      Hilda HT.. Au

      University of British Columbia

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        Dan Luciani

        University of British Columbia

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          Colin Ross

          University of British Columbia

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            Eric Jan

            University of British Columbia

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              Pascal M. Lavoie

              University of British Columbia

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