Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Abstract

The capacity of certain pathogens to exploit innate immune receptors enables them to undermine immune clearance and persist in their host, often causing disease. Here we review subversive interactions of Porphyromonas gingivalis, a major periodontal pathogen, with the complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages. Through its cell surface fimbriae, P. gingivalis stimulates Toll-like receptor-2 (TLR2) inside-out signaling which induces the highaffinity conformation of CR3. Although this activates CR3-dependent monocyte adhesion and transendothelial migration, P. gingivalis has co-opted this TLR2 proadhesive pathway for CR3 binding and intracellular entry. In CR3-deficient macrophages, the internalization of P. gingivalis is reduced 2-fold but its ability to survive intracellularly is reduced 1000-fold, indicating that CR3 is exploited by the pathogen as a relatively safe portal of entry. The interaction of P. gingivalis fimbriae with CR3 additionally inhibits production of bioactive (p70) interleukin-12, which mediates immune clearance. In vivo blockade of CR3 leads to reduced persistence of P. gingivalis in the mouse host and diminished ability to cause periodontal bone loss, the hallmark of periodontal disease. Strikingly, the ability of P. gingivalis to interact with and exploit CR3 depends upon quantitatively minor components (FimCDE) of its fimbrial structure, which predominantly consists of polymerized fimbrillin (FimA). Indeed, isogenic mutants lacking FimCDE but expressing FimA are dramatically less persistent and virulent than the wild-type organism both in vitro and in vivo. This model of immune evasion through CR3 exploitation by P. gingivalis supports the concept that pathogens evolved to manipulate innate immune function for promoting their adaptive fitness.

Structural Dissection and In Vivo Effectiveness of a Peptide Inhibitor of Porphyromonas gingivalis Adherence to Streptococcus gordonii

“…Similarly, singlespecies infection using 10 7 CFU of P. gingivalis caused a small but not statistically significant increase in bone loss over shaminfected animals. Overall, these results are consistent with previous results from Baker et al (3) and our prior studies (17,37) that showed that infection using 10 9 CFU of P. gingivalis was required to induce significant levels of bone resorption. Interestingly, dual-species infection with 10 9 CFU of S. gordonii followed by 10 7 CFU of P. gingivalis induced significant bone loss, similar to that observed in the prior single infection experiments using 10 9 CFU of P. gingivalis (17,37).…”

Purified Streptococcus pneumoniae Endopeptidase O (PepO) Enhances Particle Uptake by Macrophages in a Toll-Like Receptor 2- and miR-155-Dependent Manner

“…There is no IgG or complement involved in PepO-induced phagocytosis by macrophages. Increasing evidence shows that CR3 is also a multifunctional pattern recognition receptor of the innate immune system (40)(41)(42)(43). Once activated by its ligand, CR3 mediates a series of signaling transductions, including rearrangement of actin, which promotes phagocytosis of bacteria by macrophages and contributes to the host defense response to bacterial infection.…”

Manipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis

“…Thus, tight control of neutrophil functions and survival after bacterial clearance by induction of apoptosis, immune tolerance and resolution of inflammation, exert protective effects toward the host tissues against inflammatory tissue damage. A failure to properly regulate neutrophil abundance and turnover directly contributes to the pathogenesis of periodontitis and current literature implicates neutrophils as the main immune cell type responsible for periodontal disease progression (Hajishengallis et al, 2008b, 2015a; Scott and Krauss, 2012). …”