Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.

Abstract

Background:

Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection.

Methods:

This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates.

Results:

Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity.

Conclusion:

These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.

• Authors: Huiting Zhou, Xiaying Lu, Jie Huang, Patrick Jordan, Shurong Ma, Lingqi Xu, Fangjie Hu, Huan Gui, He Zhao, Zhenjiang Bai, H Paul Redmond, Jiang Huai Wang, Jian Wang
• Journal: Journal of inflammation research (J Inflamm Res) Vol. 15 Pg. 3829-3845 ( 2022) ISSN: 1178-7031 [Print] New Zealand
• PMID: 35836719 (Publication Type: Journal Article)
• Copyright: © 2022 Zhou et al.