Human Peptidoglycan Recognition Proteins Require Zinc to Kill Both Gram-Positive and Gram-Negative Bacteria and Are Synergistic with Antibacterial Peptides

Abstract

Mammals have four peptidoglycan recognition proteins (PGRPs or PGLYRPs), which are secreted innate immunity pattern recognition molecules with effector functions. In this study, we demonstrate that human PGLYRP-1, PGLYRP-3, PGLYRP-4, and PGLYRP-3:4 have Zn2+-dependent bactericidal activity against both Gram-positive and Gram-negative bacteria at physiologic Zn2+ concentrations found in serum, sweat, saliva, and other body fluids. The requirement for Zn2+ can only be partially replaced by Ca2+ for killing of Gram-positive bacteria but not for killing of Gram-negative bacteria. The bactericidal activity of PGLYRPs is salt insensitive and requires N-glycosylation of PGLYRPs. The LD99 of PGLYRPs for Gram-positive and Gram-negative bacteria is 0.3–1.7 μM, and killing of bacteria by PGLYRPs, in contrast to killing by antibacterial peptides, does not involve permeabilization of cytoplasmic membrane. PGLYRPs and antibacterial peptides (phospholipase A2, α- and β-defensins, and bactericidal permeability-increasing protein), at subbactericidal concentrations, synergistically kill Gram-positive and Gram-negative bacteria. These results demonstrate that PGLYRPs are a novel class of recognition and effector molecules with broad Zn2+-dependent bactericidal activity against both Gram-positive and Gram-negative bacteria that are synergistic with antibacterial peptides.

Molecular cloning and functional characterization of peptidoglycan recognition protein 6 in grass carp Ctenopharyngodon idella

“…With the availability of gene information for grass carp and also their possible relevance to PGRPs, the genes examined were NOD1 (FJ937972) and NOD2 (FJ937973), which have been suggested to bind PGNs in teleost fish (Chen et al, 2010c), pro-inflammatory cytokines IL-2 (AF486820) and TNF-a (EU047718) and antimicrobial molecules hepcidin (JQ246442), G-type lysozyme (EU835653) and perforin (AY445930), which may be produced as possible effector molecules in PGRPs induced signal pathways (Cho et al, 2005;Wang et al, 2007). The methods for QRT-PCR to examine the expression of innate immune genes were similar to those described previously (Li et al, 2013).…”

“…to mammalian NF-jB and induction of antimicrobial peptides (Tanji et al, 2007). In mammals, porcine PGRPs are involved in antimicrobial peptide expression (Sang et al, 2005), and human PGRPs were reported to kill both Gram-positive and Gram-negative bacteria by synergistic effects with antibacterial peptides (Cho et al, 2005;Wang et al, 2007). Different from insect and mammalian PGRPs, it was found that gcPGRP6 was not involved in the expression of two antibacterial peptides.…”

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

“…Unlike the TLR proteins, mammalian peptidoglycan recognition proteins (PGRPs; encoded by PGLYRP1-PGLYRP4) modulate innate immunity via PAMP recognition and microbicidal activity (19,20). Mammalian PGLYRP2 hydrolyzes bacterial peptidoglycan, with the remaining three functioning as bactericidal or bacteriostatic proteins (20)(21)(22).…”

Influence of pathogenic bacteria species present in the postpartum bovine uterus on proteome profiles

“…They recognise bacteria and bind to the unique bacterial cell-wall component, peptidoglycan (Dziarski and Gupta 2010). The extracellular protein PGLYRP1 is expressed primarily in PMN granules and has higher bactericidal activity against Gram-positive bacteria but becomes highly bactericidal for Gram-negative bacteria in the presence Zn 2þ (Wang et al 2007). There have been no reports of PGLYRP1 being expressed in endometrial tissues; therefore we assume that the protein from the cyto-brush sampling was due to the presence of PMN.…”