TheBurkholderia cenocepaciapeptidoglycan-associated lipoprotein is involved in epithelial cell attachment and elicitation of inflammation

Abstract

The Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic pathogens causing infections in people with cystic fibrosis (CF). Bcc is highly antibiotic resistant, making conventional antibiotic treatment problematic. The identification of novel targets for anti-virulence therapies should improve therapeutic options for infected CF patients. We previously identified that the peptidoglycan-associated lipoprotein (Pal) was immunogenic in Bcc infected CF patients; however, its role in Bcc pathogenesis is unknown. The virulence of a pal deletion mutant (Δpal) in Galleria mellonella was 88-fold reduced (p < .001) compared to wild type. The lipopolysaccharide profiles of wild type and Δpal were identical, indicating no involvement of Pal in O-antigen transport. However, Δpal was more susceptible to polymyxin B. Structural elucidation by X-ray crystallography and calorimetry demonstrated that Pal binds peptidoglycan fragments. Δpal showed a 1.5-fold reduced stimulation of IL-8 in CF epithelial cells relative to wild type (p < .001), demonstrating that Pal is a significant driver of inflammation. The Δpal mutant had reduced binding to CFBE41o cells, but adhesion of Pal-expressing recombinant E. coli to CFBE41o cells was enhanced compared to wild-type E. coli (p < .0001), confirming that Pal plays a direct role in host cell attachment. Overall, Bcc Pal mediates host cell attachment and stimulation of cytokine secretion, contributing to Bcc pathogenesis.

Cervicovaginal microbiota composition correlates with the acquisition of high‐risk human papillomavirus types

“…Although Burkholderia has been previously demonstrated to be a member of vaginal communities, the prevalence has been underappreciated, and its role in the community is unclear. It should be noted that Burkholderia is intrinsically resistant to clinically relevant antibiotics, which might confer a positive effect on the subversion of immune functions and the elicitation of inflammation, thus potentially facilitating the occurrence of SIL.…”

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

“…Therefore, some examples of the strictly architecture-related role of PGN (i.e., elements that physically build the static PGN structure) can be found, and they are displayed in Table 1. For instance, the disruption of the PGN-associated lipoprotein (Pal) of Burkholderia cenocepacia (belonging to the BCC) has recently been linked to a major impairment in the virulence of this species in the Galleria mellonella larva infection model, together with a dampened capacity for host cell attachment and a weaker elicitation of inflammatory cytokine secretion (35). In a similar context, some papers have related the defects in yersinia Braun's lipoprotein to an important virulence impairment in murine models of infection, which suggested that the studied knockout (KO) mutants are potential vaccine candidates for bubonic and pneumonic plague (36)(37)(38).…”

Structural and functional characterisation of SiiA, an auxiliary protein from the SPI4-encoded type 1 secretion system fromSalmonella enterica

“…remarkably different. The OmpA-like domain of PAL, on the other hand, is monomeric in -14 -solution and in the crystal structure [36]. Thus, it appears that PG-binding domains of proteins involved in ion translocation across the IM, i.e.…”