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

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

doi:10.2147/JIR.S363995

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

J Inflamm Res. 2022 Jul 7:15:3829-3845. doi: 10.2147/JIR.S363995. eCollection 2022.

Authors

Huiting Zhou^#¹, Xiaying Lu^#^{2

3}, Jie Huang^#¹, Patrick Jordan², Shurong Ma¹, Lingqi Xu¹, Fangjie Hu¹, Huan Gui¹, He Zhao¹, Zhenjiang Bai¹, H Paul Redmond², Jiang Huai Wang², Jian Wang¹

Affiliations

¹ Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, People's Republic of China.
² Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
³ Department of Physiology, Gannan Medical University, Ganzhou, People's Republic of China.

^# Contributed equally.

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.

Keywords: antimicrobial activity; epigenetic reprogramming; inflammatory response; intracellular metabolic rewiring; neonatal sepsis; trained immunity.