Secreted antigen A peptidoglycan hydrolase is essential forEnterococcus faeciumcell separation and priming of immune checkpoint inhibitor cancer therapy

Abstract

Introductory paragraphEnterococcus faeciumis a microbiota species in humans that can modulate host immunity1, but has also acquired antibiotic resistance and is a major cause of hospital-associated infections2. Notably, diverse strains ofE. faeciumproduce SagA, a highly conserved peptidoglycan hydrolase that is sufficient to promote intestinal immunity3–5and immune checkpoint inhibitor antitumor activity6. However, the essential functions of SagA inE. faeciumwere unknown. Here we report that deletion ofsagAimpairedE. faeciumgrowth and resulted in bulged and clustered enterococci due to defective peptidoglycan cleavage and cell separation. Moreover, ΔsagAshowed increased antibiotic sensitivity, yielded lower levels of active muropeptides, displayed reduced activation of the peptidoglycan pattern-recognition receptor NOD2, and failed to promote cancer immunotherapy. Importantly, plasmid-based expression of SagA, but not its catalytically-inactive mutant, restored ΔsagAgrowth, production of active muropeptides and NOD2 activation. SagA is therefore essential forE. faeciumgrowth, stress resistance and activation of host immunity.