Understanding how perinatal inflammation directs trained immunity in offspring

PROJECT SUMMARY/ABSTRACT
Nearly 11% of all pregnancies result in a preterm delivery. Prematurity is the leading cause of infant death and
disability, making it a global health priority. The majority of preterm deliveries are due to chorioamnionitis, which
involves infection and/or inflammation of the amnion, chorion and placenta. Chorioamnionitis is characterized by
acute perinatal inflammation, and results in the fetal inflammatory response syndrome (FIRS). FIRS is defined
by elevated IL-6 in the amniotic fluid and/or umbilical cord blood. FIRS is associated with an array of negative
neonatal outcomes, including white matter brain injury, sepsis, necrotizing enterocolitis and death. We have
shown that FIRS is dependent upon maternal IL-6 signaling in a murine model of sterile chorioamnionitis. We
have also shown the chorioamnionitis epigenetically re-programs human and murine neonatal monocytes and
macrophages. This epigenetic re-programming includes altered chromatin accessibility, dampened pro-
inflammatory responses and improved survival during neonatal sepsis. This is consistent with trained immunity,
where exposure to certain stimuli alters the epigenetic landscape of innate immune cells, allowing them to
respond promptly and specifically to subsequent stimuli. Trained immunity has been well-described following
exposure to the Bacillus Calmette-Guerin vaccine or the fungal ligand b-glucan, although it has also been
reported to occur following exposure to pathogen-associated molecular patterns and cytokines. Trained immunity
is generally protective against subsequent lethal infections, which is also consistent with our findings. However,
a more in-depth evaluation of chorioamnionitis-induced trained immune changes is needed to improve outcomes
in infants afflicted by this highly morbid condition. The central hypothesis of this proposal is that perinatal
inflammation induces trained immune responses in offspring monocytes/macrophages that persist into
childhood, are tissue-specific and depend on functional IL-6 signaling in both the dam and offspring.
This hypothesis will be tested with the following specific aims: 1) Determine the persistence of chorioamnionitis-
induced trained immune responses in offspring by assessing chromatin accessibility, histone tail modifications
and cell function in human monocytes through age two and murine macrophages through adulthood, 2)
Determine the tissue-specificity of chorioamnionitis-induced offspring trained immune changes by assessing
chromatin accessibility and function in neonatal bone marrow progenitors and the global transcriptional and
chromatin accessibility landscapes at a single-cell level in neonatal lung and intestine, and 3) Determine the
requirement and sufficiency of IL-6 signaling in chorioamnionitis-induced offspring monocyte/macrophage
trained immune changes by deleting IL-6 or IL-10 in murine dams or offspring, supplementing dams or offspring
with recombinant IL-6 or exposing human neonatal monocytes to recombinant IL-6 and assessing
monocyte/macrophage chromatin accessibility and function.

Grant Number: 1R56AI192497-01
NIH Institute/Center: NIH
Principal Investigator: Jennifer Bermick