Attenuated virulence of Streptococcus agalactiae deficient in D‐alanyl‐lipoteichoic acid is due to an increased susceptibility to defensins and phagocytic cells

Abstract

SummaryD -alanylation of lipoteichoic acid (LTA), allows Grampositive bacteria to modulate their surface charge, regulate ligand binding and control the electromechanical properties of the cell wall. In this study, the role of D -alanyl LTA in the virulence of the extracellular pathogen Streptococcus agalactiae was investigated. We demonstrate that a DltA -isogenic mutant displays an increased susceptibility to host defence peptides such as human defensins and animal-derived cationic peptides. Accordingly, the mutant strain is more susceptible to killing by mice bone marrow-derived macrophages and human neutrophils than the wild-type strain. In addition, the virulence of the DltA -mutant is severely impaired in mouse and neonatal rat models. This mutant was eliminated more rapidly than the wild-type strain from the lung of three-week-old mice inoculated intranasally and, consequently, is unable to induce a pneumonia. Finally, after intravenous injection of three-week-old mice, the survival of the DltA -mutant is markedly reduced in the blood in comparison to that of the wild-type strain. We hypothesize that the decreased virulence of the DltA -mutant is a consequence of its increased susceptibility to cationic antimicrobial peptides and to killing by phagocytes. These results demonstrate that the Dalanylation of LTA contributes to the virulence of S. agalactiae .

Characterization of the Bacillus subtilis YxdJ response regulator as the inducer of expression for the cognate ABC transporter YxdLM

“…The increase in D-alanyl esterification of teichoic acids caused by activation of dlt transcription should result in a neutralization of the negative charge of adjacent phosphoryl residues of this anionic polymer, eventually leading to an increased resistance of the cells to some antibiotics. In fact, mutants lacking D-alanine on teichoic acids displayed an increased sensitivity: of B. subtilis to methicillin (Wecke et al, 1997), of S. agalactiae to several cationic antimicrobial peptides (Poyart et al, 2003) and of S. aureus to gallidermin or nisin (Peschel et al, 1999).…”

Regulation of bacterial virulence gene expression by cell envelope stress responses

“…Consistent with this, dlt null mutants of Gram-positive pathogens have increased sensitivity to CAMPs, increased killing by human neutrophils and reduced virulence in animal models of infection. [156][157][158][159][160][161][162][163][164] The dlt operon is also one of the best examples of virulence genes controlled by ESRs in Gram-positive bacteria. Even though many Gram-positive ESRs are widely conserved, their target genes can vary significantly between species.…”

Antimicrobial Peptide Resistance Mechanisms of Human Bacterial Pathogens

“…Some specific surface modifications associated with decreased negative charge and increased resistance to cationic antimicrobial peptides. (Poyart et al, 2003). Similarly, inactivation of dltA in L. monocytogenes, an intracellular pathogen, led to decreased interaction with phagocytic and nonphagocytic cells and increased susceptibility to cationic AMPs (Abachin et al, 2002).…”

“…Both types of mutants are more readily phagocytosed by neutrophils and less able to establish systemic infection in mice (Kristian et al, 2003a;Kristian et al, 2003b;. A Dlt-mutant of L. monocytogenes possesses a 10,000-fold greater LD50 than the wild-type strain in murine infection (Abachin et al, 2002), and a Dlt-GBS strain was severely impaired in both mouse and neonatal rat models (Poyart et al, 2003). S. enterica mutants in PmrA lack the aminoarabinose modification of LPS associated with AMP resistance and are less virulent than wild-type following oral administration in a murine enteric infection model; however, the mutants are equally virulent when inoculated systemically (Gunn, 2001;Gunn et al, 2000), indicating a specific role for the phenotype in resistance to mucosal defenses.…”