TY - JOUR
T1 - Bacterial Peptidoglycan Fragments Differentially Regulate Innate Immune Signaling
AU - Bersch, Klare L.
AU - Demeester, Kristen E.
AU - Zagani, Rachid
AU - Chen, Shuyuan
AU - Wodzanowski, Kimberly A.
AU - Liu, Shuzhen
AU - Mashayekh, Siavash
AU - Reinecker, Hans Christian
AU - Grimes, Catherine L.
N1 - Funding Information:
This work was supported by the Delaware COBRE Program, with a grant from the National Institute of General Medical Sciences (NIGMS P20 GM104316 to C.L.G.) and the National Science Foundation (NSF 1554967). C.L.G. is a Pew Biomedical Scholar and Sloan Fellow and thanks the Pew and Sloan Foundations. H.-C.R. and C.L.G. acknowledge Grant GM138599 from the National Institutes of Health; H.C.R. acknowledges Grants AI11333 and DK068181 from the National Institutes of Health. K.L.B. and K.E.D. thank the University of Delaware for their support through the University Doctoral and Dissertation Fellowship Programs. K.E.D. and K.A.W. thank the NIH for support (5T32GM008550). Instrumentation support was provided by the Delaware COBRE and INBRE Programs, supported by the National Institute of General Medical Sciences (P30 GM110758, P20 GM104316, and P20 GM103446). We thank Lisa Hester and the University of Maryland Cytokine Core Laboratory for assistance with ELISAs, Mark Shaw and Bruce Kinngham for their help with RNA-seq, Dr. PapaNii Asare-Okai for mass spectrometry and liquid chromatography support, and especially Dr. Shi Bai for NMR support in obtaining the spectral data for 1D and 2D experiments.
Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.
PY - 2021/4/28
Y1 - 2021/4/28
N2 - The human innate immune system responds to both pathogen and commensal bacteria at the molecular level using bacterial peptidoglycan (PG) recognition elements. Traditionally, synthetic and commercially accessible PG monosaccharide units known as muramyl dipeptide (MDP) and N-glycolyl MDP (ng-MDP) have been used to probe the mechanism of innate immune activation of pattern recognition receptors, such as NOD-like receptors. However, bacterial PG is a dynamic and complex structure, with various chemical modifications and trimming mechanisms that result in the production of disaccharide-containing elements. These molecules pose as attractive targets for immunostimulatory screening; however, studies are limited because of their synthetic accessibility. Inspired by disaccharide-containing compounds produced from the gut microbe Lactobacillus acidophilus, a robust and scalable chemical synthesis of PG-based disaccharide ligands was implemented. Together with a monosaccharide PG library, compounds were screened for their ability to stimulate proinflammatory genes in bone-marrow-derived macrophages. The data reveal distinct gene induction patterns for monosaccharide and disaccharide PG units, suggesting that PG innate immune signaling is more complex than a one activator-one pathway program, as biologically relevant fragments induce transcriptional programs to different degrees. These disaccharide molecules will serve as critical immunostimulatory tools to more precisely define specialized innate immune regulatory mechanisms that distinguish between commensal and pathogenic bacteria residing in the microbiome.
AB - The human innate immune system responds to both pathogen and commensal bacteria at the molecular level using bacterial peptidoglycan (PG) recognition elements. Traditionally, synthetic and commercially accessible PG monosaccharide units known as muramyl dipeptide (MDP) and N-glycolyl MDP (ng-MDP) have been used to probe the mechanism of innate immune activation of pattern recognition receptors, such as NOD-like receptors. However, bacterial PG is a dynamic and complex structure, with various chemical modifications and trimming mechanisms that result in the production of disaccharide-containing elements. These molecules pose as attractive targets for immunostimulatory screening; however, studies are limited because of their synthetic accessibility. Inspired by disaccharide-containing compounds produced from the gut microbe Lactobacillus acidophilus, a robust and scalable chemical synthesis of PG-based disaccharide ligands was implemented. Together with a monosaccharide PG library, compounds were screened for their ability to stimulate proinflammatory genes in bone-marrow-derived macrophages. The data reveal distinct gene induction patterns for monosaccharide and disaccharide PG units, suggesting that PG innate immune signaling is more complex than a one activator-one pathway program, as biologically relevant fragments induce transcriptional programs to different degrees. These disaccharide molecules will serve as critical immunostimulatory tools to more precisely define specialized innate immune regulatory mechanisms that distinguish between commensal and pathogenic bacteria residing in the microbiome.
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U2 - 10.1021/acscentsci.1c00200
DO - 10.1021/acscentsci.1c00200
M3 - Article
C2 - 34056099
AN - SCOPUS:85105090891
SN - 2374-7943
VL - 7
SP - 688
EP - 696
JO - ACS Central Science
JF - ACS Central Science
IS - 4
ER -