Abstract
Lysozymes are ancient and important components of the innate immune system of animals that hydrolyze peptidoglycan, the major bacterial cell wall polymer. Bacteria engaging in commensal or pathogenic interactions with an animal host have evolved various strategies to evade this bactericidal enzyme, one recently proposed strategy being the production of lysozyme inhibitors. We here report the discovery of a novel family of bacterial lysozyme inhibitors with widespread homologs in gram-negative bacteria. First, a lysozyme inhibitor was isolated by affinity chromatography from a periplasmic extract of Salmonella Enteritidis, identified by mass spectrometry and correspondingly designated as PliC (periplasmic lysozyme inhibitor of c-type lysozyme). A pliC knock-out mutant no longer produced lysozyme inhibitory activity and showed increased lysozyme sensitivity in the presence of the outer membrane permeabilizing protein lactoferrin. PliC lacks similarity with the previously described Escherichia coli lysozyme inhibitor Ivy, but is related to a group of proteins with a common conserved COG3895 domain, some of them predicted to be lipoproteins. No function has yet been assigned to these proteins, although they are widely spread among the Proteobacteria. We demonstrate that at least two representatives of this group, MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, also possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli. Interestingly, mliC of Salmonella Typhi was picked up earlier in a screen for genes induced during residence in macrophages, and knockout of mliC was shown to reduce macrophage survival of S. Typhi. Based on these observations, we suggest that the COG3895 domain is a common feature of a novel and widespread family of bacterial lysozyme inhibitors in gram-negative bacteria that may function as colonization or virulence factors in bacteria interacting with an animal host.
Highlights
Lysozymes (EC 3.2.1.17) hydrolyse the b-(1,4) glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycan, the major cell wall polymer in the Bacteria
Bacteria colonizing or infecting an animal host have developed various ways to overcome lysozyme action, a recently proposed mechanism being the production of lysozyme inhibitors
We here report the discovery of a novel and distinct family of bacterial lysozyme inhibitors that is widely distributed among the Proteobacteria, including several major pathogens
Summary
Lysozymes (EC 3.2.1.17) hydrolyse the b-(1,4) glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycan, the major cell wall polymer in the Bacteria. Peptidoglycan forms a network that surrounds the entire bacterial cell, and its hydrolysis by lysozyme renders bacteria sensitive to lysis driven by turgor pressure. Most gram-negative bacteria are not susceptible to the action of lysozyme alone because their outer membrane prevents access of the enzyme to the peptidoglycan layer. This barrier has been overcome in the innate immune systems of animals by the production of accessory antibacterial proteins which permeabilize the outer membrane, such as lactoferrin. Some natural lysozymes as well as chemically or genetically modified hen egg white lysozyme (HEWL) have been reported to be active against gram-negative bacteria even in the absence of such permeabilizers [1,2,3,4]
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