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Human Peptidoglycan Recognition Proteins Require Zinc to Kill Both Gram-Positive and Gram-Negative Bacteria and Are Synergistic with Antibacterial Peptides¹

Indiana University School of Medicine, Northwest Campus, Gary, IN 46408

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, - and -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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants AI28797 and AI56395 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Roman Dziarski, Indiana University School of Medicine, Northwest Campus, 3400 Broadway, Gary, IN 46408. E-mail address: rdziar{at}iun.edu

³ Abbreviations used in this paper: PGRP or PGLYRP, peptidoglycan recognition proteins; BPI, bactericidal permeability-increasing protein; HBD-3, human -defensin-3; HNP-1, human neutrophil protein-1 (-defensin); LTA, lipoteichoic acid; MurNAc, N-acetylmuramic acid; LB, Luria-Bertani; PLA₂, group IIA phospholipase A₂.