Staphylococcal Biofilm Exopolysaccharide Protects against Caenorhabditis elegans Immune Defenses

Jakob Begun,Costi D Sifri,Dietrich Mack,Frederick M Ausubel,Holger Rohde,Stephen B Calderwood,Jessica M Gaiani,David S Schneider

doi:10.1371/journal.ppat.0030057

Abstract

Staphylococcus epidermidis and Staphylococcus aureus are leading causes of hospital-acquired infections that have become increasingly difficult to treat due to the prevalence of antibiotic resistance in these organisms. The ability of staphylococci to produce biofilm is an important virulence mechanism that allows bacteria both to adhere to living and artificial surfaces and to resist host immune factors and antibiotics. Here, we show that the icaADBC locus, which synthesizes the biofilm-associated polysaccharide intercellular adhesin (PIA) in staphylococci, is required for the formation of a lethal S. epidermidis infection in the intestine of the model nematode Caenorhabditis elegans. Susceptibility to S. epidermidis infection is influenced by mutation of the C. elegans PMK-1 p38 mitogen-activated protein (MAP) kinase or DAF-2 insulin-signaling pathways. Loss of PIA production abrogates nematocidal activity and leads to reduced bacterial accumulation in the C. elegans intestine, while overexpression of the icaADBC locus in S. aureus augments virulence towards nematodes. PIA-producing S. epidermidis has a significant survival advantage over ica-deficient S. epidermidis within the intestinal tract of wild-type C. elegans, but not in immunocompromised nematodes harboring a loss-of-function mutation in the p38 MAP kinase pathway gene sek-1. Moreover, sek-1 and pmk-1 mutants are equally sensitive to wild-type and icaADBC-deficient S. epidermidis. These results suggest that biofilm exopolysaccharide enhances virulence by playing an immunoprotective role during colonization of the C. elegans intestine. These studies demonstrate that C. elegans can serve as a simple animal model for studying host–pathogen interactions involving staphylococcal biofilm exopolysaccharide and suggest that the protective activity of biofilm matrix represents an ancient conserved function for resisting predation.

Highlights

Staphylococci are a predominant cause of hospitalacquired infections, those associated with implanted medical devices and catheters
We demonstrate that the ability of Staphylococcus epidermidis to produce a lethal infection within the intestinal tract of the roundworm Caenorhabditis elegans depends on the S. epidermidis intercellular adhesion locus, which is responsible for the synthesis of the principal exopolysaccharide of staphylococcal biofilm, polysaccharide intercellular adhesin (PIA)
Using a collection of bacterial and nematode mutants, we show that PIA promotes infection by working against protective immune factors controlled by the C. elegans SEK-1 PMK-1 p38 mitogen-activated protein kinase pathway

Summary

Introduction

Staphylococci are a predominant cause of hospitalacquired infections, those associated with implanted medical devices and catheters. The ability of staphylococci, Staphylococcus epidermidis, to form biofilm on biotic and abiotic surfaces appears to be critical for the establishment of these infections and to contribute to their persistence by protecting S. epidermidis from antibiotics and host defenses [1,2]. PIA mediates intercellular adhesion essential for biofilm accumulation, and has a role in primary attachment to certain hydrophilic abiotic polymer surfaces [3,4,5,6,7]. The S. epidermidis intercellular adhesion locus (ica), consisting of the biosynthetic operon icaADBC and the regulatory gene icaR [5,8,9], is required for PIA biosynthesis as well as for biofilm formation in vitro and in several animal models of S. epidermidis infection [6,10,11]. Epidemiologic studies have shown that the presence of the ica locus is associated with pathogenic strains of S. epidermidis [14,15,16]

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