OmpA-Like Proteins of Porphyromonas gingivalis Mediate Resistance to the Antimicrobial Peptide LL-37

Abstract

Subgingival bacteria are continually exposed to gingival crevicular fluids that are derived from serum, which contain various bactericidal agents. The periodontopathic bacterium Porphyromonas gingivalis has been demonstrated to possess a variety of abilities to resist bactericidal agents, due to which it is able to propagate in the subgingival environment. We previously demonstrated that the major surface glycoproteins of P. gingivalis—Pgm6 and Pgm7, also called outer membrane protein A-like proteins (OmpALPs)—mediate resistance to the bactericidal activity of human serum, but their precise role remains unknown. In this study, we investigated the sensitivity of the wild-type and Pgm6/Pgm7-deficient P. gingivalis strains toward major antimicrobial peptides in the oral cavity, human β-defensins (hBDs) 1-3, and human cathelicidin LL-37. hBDs showed a considerably weak bactericidal activity against both bacterial strains. LL-37 also showed a weak activity against the wild-type strain; however, it showed a significant activity against the Pgm6/Pgm7-deficient strain. In the Pgm6/Pgm7-deficient strain, LL-37 remarkably accumulated on the bacterial cell surface, which may result in the destruction of the outer membrane. Additionally, the bactericidal activity of hBDs against the Pgm6/Pgm7-deficient strain was found to be synergistically promoted in the presence of LL-37. Our results suggest that OmpALPs specifically protect P. gingivalis from the bactericidal activity of LL-37; thus, P. gingivalis may adeptly survive in LL-37-producing subgingival environments.

The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent

“…When LL-37 binds to AbOmpA, it can inhibit motility and adhesion of A. baumannii; although A. baumannii is considered a non-motile bacterium, it has the capability to migrate under certain conditions [63]. In Escherichia coli and other enterobacteria, OmpA acts as an adhesion and invasion [63], and outer membrane protein A-like proteins (OmpALPs) in Porphyromonas gingivalis serves as a protection against LL-37 accumulation on the surface of the cell [64]. Mutations in both the ompA [63] and OmpALP [64] results in a greater sensitivity to LL-37.…”

“…In Escherichia coli and other enterobacteria, OmpA acts as an adhesion and invasion [63], and outer membrane protein A-like proteins (OmpALPs) in Porphyromonas gingivalis serves as a protection against LL-37 accumulation on the surface of the cell [64]. Mutations in both the ompA [63] and OmpALP [64] results in a greater sensitivity to LL-37. It is suggested that in the absence of ompA, LL-37 will bind to other OMPs that exhibit higher permeability and pore-forming ability, which increases the level of cell death [63].…”

“…It is suggested that in the absence of ompA, LL-37 will bind to other OMPs that exhibit higher permeability and pore-forming ability, which increases the level of cell death [63]. In the absence of OmpALPs, LL-37 can accumulate on the cell surface, leading to enhanced destruction of the cell surface [64]. Moreover, Urashima et al report that ompT expression augments the production of OmpT-loaded OMVs, contributing to LL-37 tolerance.…”

“…While metalloproteases assist in the pathogenesis of several bacteria, metalloprotease inhibitors can be effective in blocking the harmful effects on LL-37, such as the EDTA, 1,10-phenanthroline [29] and LasB inhibitors [72]. Other proteases implicated in LL-37 resistance include the ClpXP intracellular protease [74], the SpeB [32] and SspB secreted cysteine proteases [75], and the PASP [64], aureolysin and V8 secreted proteases [75].…”

Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis

“…Since LL-37 exerts bactericidal and antiinflammatory activities by binding to LPS, the degradation of this peptide also abolishes its anti-inflammatory effect and promotes the release of TNF-a, contributing to the development of late-onset periodontitis (Koneru et al, 2017). In addition to T. forsythia, P. gingivalis has evolved a mechanism to abolish the bactericidal activity of LL-37 by its outer membrane protein A-like proteins, preventing the accumulation of LL-37 on the bacterial surface (Horie et al, 2018). These bacteria can also inhibit the serine protease activity.…”