D-alanylation of Teichoic Acids in Bacilli impedes the immune sensing of peptidoglycan in Drosophila

Abstract

15Modification of cell wall components is a prominent mean for pathogens to hinder host immune 16 defenses. Here, using the Drosophila model, we aimed at characterizing the role of D-alanine 17 esterification of teichoic acids (TAs) in the resistance of Bacillus thuringiensis to host defenses 18 in vivo. We show that, by preventing cationic antimicrobial effectors-mediated bacterial lysis, 19 this cell wall modification also limits the release of peptidoglycan immunostimulatory fragments 20 thus impeding their sensing and the subsequent induction of the IMD-NF-B pathway. 21Interestingly, we show that this strategy is also adopted by Lactobacillus plantarum, a bona fide 22 commensal, to fine-tune its immunomodulatory potential in the Drosophila gut. Markedly, we 23show that the D-alanylation of TAs is essential for the resistance of L. plantarum to gut 24 lysozyme. Altogether our data shed light on the mechanism underlying the persistence and the 25 low immunostimulatory potential of L. plantarum in the Drosophila gut. 26 muramidase activity, which cleaves the β-(

Resistance to host antimicrobial peptides mediates resilience of gut commensals during infection and aging inDrosophila

“…One of the identified AMPsensitive mutants had a transposon insertion in the dlt operon, which has been previously implicated in the sensitivity to AMPs in several Gram-positive bacteria 37 . Consequently, dlt mutants in several pathogens exhibit attenuated virulence 23,48,49 . The dlt operon was also found to be essential for the commensal establishment in the host gut, namely for L. reuteri in the mouse intestine 50 and for L. casei in the rabbit gut 51 a stronger immune response compared to wild-type L. plantarum 23 .…”

“…Consequently, dlt mutants in several pathogens exhibit attenuated virulence 23,48,49 . The dlt operon was also found to be essential for the commensal establishment in the host gut, namely for L. reuteri in the mouse intestine 50 and for L. casei in the rabbit gut 51 a stronger immune response compared to wild-type L. plantarum 23 . Our results similarly support the essential role of the dlt operon in L. plantarum in colonizing the Drosophila gut.…”

“…However, the microbiota remains only a mild inducer of the AMP response, suggesting that flies deploy immune tolerance mechanisms to commensals. Indeed, while commensals stimulate a weak AMP response, they induce a strong expression of negative regulators of the Imd pathway 19,22,23 . These negative regulators, like the PGN-degrading enzymes PGRP-SC1 and PGRP-LB, maintain a low basal level of immunostimulatory PGN, thus preventing the overactivation of the Imd pathway to the gut microbiota [24][25][26] .…”

The fliK Gene Is Required for the Resistance of Bacillus thuringiensis to Antimicrobial Peptides and Virulence in Drosophila melanogaster

“…Bt407 dltX and Bt407 dlt have been described (Kamar et al, 2017;Attieh et al, 2019). Bt407 fla mutant was provided by Dr. Michel Gohar (Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France) (Houry et al, 2010).…”

Mechanism of immune modulation in macrophages by Enterococcus faecalis

“…Similarly, MprF1 and MprF2 in E. faecalis can also reduce negative net charge of the membrane protein through aminoacylation of PG and therefore lead to repulsion of cationic AMPs (Bao et al, 2012;Kandaswamy et al, 2013;Rashid et al, 2017). Furthermore, D-alanylation of teichoic acid by D-alanine-D-alanyl carrier protein ligase, encoded by the dltA operon, in Gram-positive bacteria including S. aureus, Group A Streptococcus (GAS), E. faecalis and L. plantarum helps in repulsion of cationic AMPs, promoting resistance to neutrophil killing and increasing adherence to eukaryotic cells (Fabretti et al, 2006) ( Attieh et al, 2019;Kristian et al, 2005;Peschel et al, 1999).…”