Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
Jeanne Salje
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Kavita J Rangan
Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States
Deena A Oren
Structural Biology Resource Center, The Rockefeller University, New York, United States
Jin Young Kang
Laboratory of Molecular Biophysics, The Rockefeller University, New York, United States
Virginia A Pedicord
Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, United States; Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, United Kingdom
We discovered that Enterococcus faecium (E. faecium), a ubiquitous commensal bacterium, and its secreted peptidoglycan hydrolase (SagA) were sufficient to enhance intestinal barrier function and pathogen tolerance, but the precise biochemical mechanism was unknown. Here we show E. faecium has unique peptidoglycan composition and remodeling activity through SagA, which generates smaller muropeptides that more effectively activates nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in mammalian cells. Our structural and biochemical studies show that SagA is a NlpC/p60-endopeptidase that preferentially hydrolyzes crosslinked Lys-type peptidoglycan fragments. SagA secretion and NlpC/p60-endopeptidase activity was required for enhancing probiotic bacteria activity against Clostridium difficile pathogenesis in vivo. Our results demonstrate that the peptidoglycan composition and hydrolase activity of specific microbiota species can activate host immune pathways and enhance tolerance to pathogens.
