Integrin ligation activates both cell adhesion and signal transduction, in part through reorganization of the actin cytoskeleton. Plastins (also known as fimbrins) are actin-crosslinking proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. Here we show that plastin-deficient polymorphonuclear neutrophils (PMN) are deficient in killing the bacterial pathogen Staphylococcus aureus in vivo and in vitro, despite normal phagocytosis. Like integrin beta2-deficient PMN, plastin-deficient PMN cannot generate an adhesion-dependent respiratory burst, because of markedly diminished integrin-dependent syk activation. Unlike beta2(-/-) PMN, plastin-deficient PMN adhere and spread normally. Deficiency of plastin thus separates the classical integrin receptor functions of adhesion and spreading from intracellular signal transduction.
Quorum sensing triggers virulence factor expression in medically important bacterial pathogens in response to a density-dependent increase in one or more autoinducing pheromones. Here, we show that phagocyte-derived oxidants target these autoinducers for inactivation as an innate defense mechanism of the host. In a skin infection model, expression of phagocyte NADPH oxidase, myeloperoxidase, or inducible nitric oxide synthase was critical for defense against a quorum-sensing pathogen, Staphylococcus aureus, but not for defense against a quorum sensing-deficient mutant. A virulence-inducing peptide of S. aureus was inactivated in vitro and in vivo by reactive oxygen and nitrogen intermediates, including HOCl and ONOO ؊ . Inactivation of the autoinducer prevented both the up-regulation of virulence gene expression and the downstream sequelae. MS analysis of the inactivated peptide demonstrated that oxidation of the C-terminal methionine was primarily responsible for loss of activity. Treatment of WT but not NADPH oxidase-deficient mice with N-acetyl methionine to scavenge the inhibitory oxidants increased in vivo quorum sensing independently of the bacterial burden at the site of infection. Thus, oxidant-mediated inactivation of an autoinducing peptide from S. aureus is a critical innate defense mechanism against infection with this pathogen.B acteria sense each other and their numbers by means of a cell-to-cell communication mechanism, called quorum sensing, that is mediated by secretion of small, diffusible pheromones or autoinducers (1, 2). At a concentration threshold that reflects a sufficient quorum of bacteria, the autoinducers trigger behaviors that are primarily effective at high population densities, including the secretion of virulence factors (1-6). Whereas the genetic systems that regulate quorum sensing in many bacterial pathogens are undergoing intensive investigation, specific effector mechanisms in mammalian hosts that limit densitydependent virulence have not been defined. We speculated that an important contribution of innate immunity in defense against bacterial infection would be to inhibit autoinducer signaling of virulence gene expression.Staphylococcus aureus is a medically important bacterial pathogen that uses quorum sensing to regulate virulence in several experimental models of infection (4, 7-9). The agr operon, which is responsible in part for this regulation, combines secretion of an autoinducing thiolactone peptide (AIP) with a two-component regulatory pathway to generate a regulatory RNA transcript, RNAIII, that is the effector of the operon (10-12). S. aureus strains can be categorized into four groups based on the amino acid sequence of the AIP produced (12). Whereas clinical isolates are enriched for the type I AIP (13, 14), all groups are represented in human disease (14). Under conditions of high AIP concentration, i.e., high bacterial density, RNAIII down-regulates gene expression encoding for surface adhesins while up-regulating those encoding for capsule production, secrete...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.