title: Role of mouse peptidoglycan recognition protein PGLYRP2 in the innate immune response to Salmonella enterica serovar Typhimurium infection in vivo.
abstract: Peptidoglycan recognition proteins (PGRPs) are a family of innate pattern recognition molecules that bind bacterial peptidoglycan. While the role of PGRPs in Drosophila innate immunity has been extensively studied, how the four mammalian PGRP proteins (PGLYRP1 to PGLYRP4) contribute to host defense against bacterial pathogens in vivo remains poorly understood. PGLYRP1, PGLYRP3, and PGLYRP4 are directly bactericidal in vitro, whereas PGLYRP2 is an N-acetylmuramyl-L-alanine amidase that cleaves peptidoglycan between the sugar backbone and the peptide stem. Because PGLYRP2 cleaves muramyl peptides detected by host peptidoglycan sensors Nod1 and Nod2, we speculated that PGLYRP2 may act as a modifier of Nod1/Nod2-dependent innate immune responses. We investigated the role of PGLYRP2 in Salmonella enterica serovar Typhimurium-induced colitis, which is regulated by Nod1/Nod2 through the induction of an early Th17 response. PGLYRP2 did not contribute to expression of Th17-associated cytokines, interleukin-22 (IL-22)-dependent antimicrobial proteins, or inflammatory cytokines. However, we found that Pglyrp2-deficient mice displayed significantly enhanced inflammation in the cecum at 72 h postinfection, reflected by increased polymorphonuclear leukocyte (PMN) infiltration and goblet cell depletion. Pglyrp2 expression was also induced in the cecum of Salmonella-infected mice, and expression of green fluorescent protein under control of the Pglyrp2 promoter was increased in discrete populations of intraepithelial lymphocytes. Lastly, Nod2(-/-) Pglyrp2(-/-) mice displayed increased susceptibility to infection at 24 h postinfection compared to Pglyrp2(-/-) mice, which correlated with increased PMN infiltration and submucosal edema. Thus, PGLYRP2 plays a protective role in vivo in the control of S. Typhimurium infection through a Nod1/Nod2-independent mechanism.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jooeun
authors.initials: J
authors.lastname: Lee
authors.forename: Kaoru
authors.initials: K
authors.lastname: Geddes
authors.forename: Catherine
authors.initials: C
authors.lastname: Streutker
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
mesh_terms: D000818:Animals; D002432:Cecum / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009238:N-Acetylmuramoyl-L-alanine Amidase; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms
chemical_list: D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D011506:Proteins; D009238:N-Acetylmuramoyl-L-alanine Amidase; C416533:Pglyrp2 protein, mouse