A critical role for peptidoglycan N-deacetylation in Listeria evasion from the host innate immune system

Abstract

Listeria monocytogenes is a human intracellular pathogen that is able to survive in the gastrointestinal environment and replicate in macrophages, thus bypassing the early innate immune defenses. Peptidoglycan (PG) is an essential component of the bacterial cell wall readily exposed to the host and, thus, an important target for the innate immune system. Characterization of the PG from L. monocytogenes demonstrated deacetylation of N-acetylglucosamine residues. We identified a PG N-deacetylase gene, pgdA, in L. monocytogenes genome sequence. Inactivation of pgdA revealed the key role of this PG modification in bacterial virulence because the mutant was extremely sensitive to the bacteriolytic activity of lysozyme, and growth was severely impaired after oral and i.v. inoculations. Within macrophage vacuoles, the mutant was rapidly destroyed and induced a massive IFN-␤ response in a TLR2 and Nod1-dependent manner. Together, these results reveal that PG N-deacetylation is a highly efficient mechanism used by Listeria to evade innate host defenses. The presence of deacetylase genes in other pathogenic bacteria indicates that PG N-deacetylation could be a general mechanism used by bacteria to evade the host innate immune system. cytokine ͉ macrophage ͉ pathogenesis ͉ virulence ͉ cell wall

Peptidoglycan N-acetylglucosamine deacetylation decreases autolysis in Lactococcus lactis

“…The degree of peptidoglycan GlcNAc deacetylation in L. lactis strain IL6288 (9.8 %) was low compared to that observed in S. pneumoniae (over 80 % in strain R36A; Vollmer & Tomasz, 2000), B. cereus (40-100 %; Hayashi et al, 1973) and L. monocytogenes (50 %; Boneca et al, 2007). However, this appears to be sufficient to modulate the sensitivity of L. lactis cells to lysozyme and to AcmA autolysin.…”

“…Deacetylation of peptidoglycan aminosugars has previously been shown to affect the hydrolytic activity of PGHs with different specificities, either positively or negatively. For example, de-N-acetylation of peptidoglycan GlcNAc confers resistance to lysozyme, an exogenous muramidase, upon several bacterial species, such as S. pneumoniae (Vollmer & Tomasz, 2000), Bacillus cereus (Hayashi et al, 1973), Listeria monocytogenes (Boneca et al, 2007) and L. lactis (this study). In contrast, a muramidase purified from Clostridium acetobutylicum has been found to act on non-acetylated peptidoglycan alone (Croux et al, 1992).…”

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…In macrophages, the ΔpgdA mutant was rapidly killed and induced a very strong IFNβ response in a TLR2-and Nod1-dependent manner. 209 Listeria peptidoglycan N-deacetylation appears thus critical for evasion of the host innate defenses. p60 has been shown to indirectly enhance natural killer (NK) cell activation and increase innate IFNγ production, induce proinflammatory cytokines and modulate host immune response through an unknown mechanism.…”

“…The molecular characterization of the L. monocytogenes peptidoglycan further evidenced the deacetylation of N-acetylglucosamine residues. 209 Peptidoglycan is the main structural component of the bacterial cell wall and is easily exposed to the host, constituting an important target for the innate immune system. Inactivation of the pgdA gene revealed the critical role of peptidoglycan deacetylation in bacterial virulence.…”

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

“…In Staphylococcus epidermidis, exopolysaccharide deacetylation has been shown to be crucial for biofilm formation, surface colonization, resistance to neutrophil phagocytosis, and resistance to cationic antimicrobial peptides (AMPs) (Vuong et al, 2004). Protection against host defences by peptidoglycan deacetylases has also been reported for Listeria monocytogenes (Boneca et al, 2007) and Streptococcus pneumoniae (Vollmer & Tomasz, 2000. In both cases, modification of the cell wall by a peptidoglycan deacetylase (PgdA) provides increased resistance to lysozyme and is essential for full virulence of the pathogen in a small animal model of infection.…”