Article

The Legionella pneumophila EnhC protein interferes with immunostimulatory muramyl peptide production to evade innate immunity.

Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02115, USA.
Cell host & microbe (Impact Factor: 12.19). 08/2012; 12(2):166-76. DOI: 10.1016/j.chom.2012.06.004
Source: PubMed

ABSTRACT Successful pathogens have evolved to evade innate immune recognition of microbial molecules by pattern recognition receptors (PRR), which control microbial growth in host tissues. Upon Legionella pneumophila infection of macrophages, the cytosolic PRR Nod1 recognizes anhydro-disaccharide-tetrapeptide (anhDSTP) generated by soluble lytic transglycosylase (SltL), the predominant bacterial peptidoglycan degrading enzyme, to activate NF-κB-dependent innate immune responses. We show that L. pneumophila periplasmic protein EnhC, which is uniquely required for bacterial replication within macrophages, interferes with SltL to lower anhDSTP production. L. pneumophila mutant strains lacking EnhC (ΔenhC) increase Nod1-dependent NF-κB activation in host cells, while reducing SltL activity in a ΔenhC strain restores intracellular bacterial growth. Further, L. pneumophila ΔenhC is specifically rescued in Nod1- but not Nod2-deficient macrophages, arguing that EnhC facilitates evasion from Nod1 recognition. These results indicate that a bacterial pathogen regulates peptidoglycan degradation to control the production of PRR ligands and evade innate immune recognition.

Download full-text

Full-text

Available from: James T Park, Oct 06, 2014
0 Followers
 · 
151 Views
  • Source
    • "NOD engagement of PAMPs activates receptor interacting serine/threonine kinase (RICK), resulting in activation of NFkB-mediated transcription (Kersse et al., 2011) (Fig. 2). Several bacteria modify peptidoglycan in order to avoid being recognized by NODs (Wolfert et al., 2007), and Legionella pneumophila encodes a periplasmic protein EnhC that inhibits degradation of peptidoglycan thereby preventing production of PAMPs (Liu et al., 2012). A third approach is to inhibit TLR signalling by direct interactions between secreted bacterial effector molecules and the host TLR receptors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The human body is constantly challenged by a variety of commensal and pathogenic microorganisms that trigger the immune system. Central in the first line of defense is the pattern-recognition receptor (PRR)-induced stimulation of the nuclear factor κB (NFκB) pathway, leading to NFκB activation. The subsequent production of pro-inflammatory cytokines and/or antimicrobial peptides results in recruitment of professional phagocytes and bacterial clearance. To overcome this, bacteria have developed mechanisms for targeted interference in every single step in the PRR-NFκB pathway to dampen host inflammatory responses. This review aims to briefly overview the PRR-NFκB pathway in relation to the immune response and give examples of the diverse bacterial evasion mechanisms including changes in the bacterial surface, decoy production and injection of effector molecules. Targeted regulation of inflammatory responses is needed and bacterial molecules developed for immune evasion could provide future anti-inflammatory agents.
    Microbiology 07/2013; 159(Pt 10). DOI:10.1099/mic.0.069369-0 · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The peptidoglycan cell wall maintains turgor pressure and cell shape of most bacteria. Cell wall hydrolases are essential, together with synthases, for growth and daughter cell separation. Recent work in diverse organisms has uncovered new cell wall hydrolases that act autonomously or on neighboring cells to modulate invasion of prey cells, cell shape, innate immune detection, intercellular communication, and competitor lysis. The hydrolases involved in these processes catalyze the cleavage of bonds throughout the sugar and peptide moities of peptidoglycan. Phenotypes associated with these diverse hydrolases reveal new functions of the bacterial cell wall beyond growth and division.
    Trends in Microbiology 08/2012; 20(11):540-7. DOI:10.1016/j.tim.2012.08.003 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The intracellular bacterial agent of Q fever, Coxiella burnetii, translocates effector proteins into its host cell cytosol via a Dot/Icm type IV secretion system (T4SS). The T4SS is essential for parasitophorous vacuole formation, intracellular replication, and inhibition of host cell death, but effectors mediating these events remain largely undefined. Six Dot/Icm substrate-encoding genes were recently discovered on the C. burnetii cryptic QpH1 plasmid, three of which are conserved among all C. burnetii isolates, suggesting they are critical for conserved pathogen functions. However, remaining hypothetical proteins encoded by plasmid genes have not been assessed for their potential as T4SS substrates. In the current study, we further defined the T4SS effector repertoire encoded by the C. burnetii QpH1, QpRS, and QpDG plasmids that were originally isolated from acute disease, chronic disease, and severely attenuated isolates, respectively. Hypothetical proteins, including those specific to QpRS or QpDG, were screened for translocation using the well-established Legionella pneumophila T4SS secretion model. In total, six novel plasmid-encoded proteins were translocated into macrophage-like cells by the Dot/Icm T4SS. Four newly identified effectors are encoded by genes only present on the QpDG plasmid from severely attenuated Dugway isolates, suggesting presence of specific effectors correlates with decreased virulence. These results further support a critical role for extrachromosomal elements in C. burnetii pathogenesis.
    Journal of bacteriology 05/2013; DOI:10.1128/JB.00180-13 · 2.69 Impact Factor
Show more