Periodontitis is a highly prevalent infectious, inflammatory disease of the gum tissue supporting the teeth that can lead to tissue destruction, alveolar bone resorption, and eventual tooth loss in adults 1, imposing a significant impact on public health and an immense economic burden 2, 3. Further, over the years, evidence has accumulated that shows periodontitis is epidemiologically associated with several chronic inflammation-driven disorders, including cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, preterm birth, and certain cancers 4. Periodontitis is driven by a feedforward loop between the periodontal microbiota and host factors in the subgingival niche that favors the emergence and persistence of microbial dysbiosis and increases in a synergistic community of virulent bacteria below the gum line 5, 6. It is thought to be the consequence of inflammatory destruction of host components, such as collagen and heme-containing compounds, and increased gingival crevicular fluid (serum exudates) in the gingival crevice that provides additional nutrients and promotes the selective expansion of periodontal pathogens, while linking local infections/inflammation of periodontal tissues with the systemic inflammatory burden in periodontal patients 5. With that, it is becoming critical to understand pathophysiology of periodontal pathogens and their complex relationship with host immune components.
The conventional culture-based and molecular approaches identified a list of candidate pathogens associated with periodontitis. Among recognized pathogens, the Gram-negative anaerobe Porphyromonas gingivalis (Pg) has been strongly implicated in the onset and development of chronic periodontitis as well as several systemic diseases in adults upon producing an array of virulence factors, most notably, lipopolysaccharides (LPS) and potent proteases known as gingipains 5, 7, 8. But how Pg can persist below the gum line and evade immune responses remains largely unknown. In bacteria, the strategic changes in the cell envelope composition and associated cellular processes are controlled by cyclic dinucleotide (CDN) second messengers, such as cyclic-3′,5′-diguanylic acid (c-di-GMP), and cyclic di-3',5'-adenylic acid (c-di-AMP). Indeed, these second messengers protect pathogens from stresses, antibiotics, and host defense mechanisms and determine many aspects of bacterial pathogenesis via regulating lifestyle, phenotype, the cell envelope composition, and the production of capsular, exopolysaccharides, and lipopolysaccharides 9, 10. However, our understanding of CDN signaling systems in the periodontal microbiome and their biological significance in the development of oral infections remain largely unknown.
Our present study provides the first glimpse into the scheme of second messenger signaling in Pg and perhaps other Bacteroidetes. Our findings indicate that c-di-AMP signaling promotes the fitness of the residents of the oral cavity and the development of a pathogenic community. We show that shifts in c-di-AMP signaling change the integrity and homeostasis of cell envelope, importantly, the structure and immunoreactivity of the lipopolysaccharide (LPS) layer, as well as virulence potential. These findings are important because numerous studies have shown that Pg LPS is one of the major immunostimulatory factors that can interact with Toll-like receptor 4 (TLR4) on immune and non-immune cells, stimulate production of inflammatory cytokines, and regulate osteoclast differentiation and activity (the principal bone resorptive cell) 11, 12. Surprisingly, Pg LPS may unusually act as an agonist for TLR2 13, 14. Several studies have addressed the structural heterogeneity of Pg LPS which has fueled the notion that Pg LPS structural variants display unique properties by which Pg can selectively modify and evade host inflammatory responses via changing the ratio of agonistic and antagonistic LPS variants in response to biologically relevant stimuli 15-19. In addition, LPS heterogeneity is thought to be the cause of a highly unusual and differential immune and host response by different cell types, which can lead to a range of pro- and anti-inflammatory outcomes. Such inconsistency among several findings complicated the interpretation of innate host responses to Pg LPS and resulted in an incomplete understanding of Pg’s contribution to the pathology of periodontitis. Indeed, LPS modification has been considered as an essential aspect of bacterial pathoadaptation by which pathogens can disguise themselves from host detection, regulate virulence and immunostimulatory effects, or protect themselves from host defense mechanisms, antimicrobials, and environmental stresses 20, 21. We are working to understand the mechanisms by which periodontal pathogens evade the immune system and contribute to the manipulation of the innate immune responses. Our present work reveals a novel pathoadaptive mechanism by which periodontal pathogens, and perhaps other Bacteroidetes of the human microbiome can persist in host and promote infections and inflammation.
Read the paper here:
Moradali, M.F., Ghods, S., Bähre, H. et al. Atypical cyclic di-AMP signaling is essential for Porphyromonas gingivalis growth and regulation of cell envelope homeostasis and virulence. npj Biofilms Microbiomes 8, 53 (2022). https://doi.org/10.1038/s41522-022-00316-w
- Lamont, R. J.; Hajishengallis, G., Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 2015, 21 (3), 172-83.
- Brown, L. J.; Johns, B. A.; Wall, T. P., The economics of periodontal diseases. Periodontol 2000 2002, 29, 223-34.
- Papapanou, P. N., Systemic effects of periodontitis: lessons learned from research on atherosclerotic vascular disease and adverse pregnancy outcomes. Int Dent J 2015, 65 (6), 283-91.
- Kumar, P. S., Oral microbiota and systemic disease. Anaerobe 2013, 24, 90-93.
- Lamont, R. J.; Koo, H.; Hajishengallis, G., The oral microbiota: dynamic communities and host interactions. Nature reviews. Microbiology 2018, 16 (12), 745-759.
- Abusleme, L.; Dupuy, A. K.; Dutzan, N.; Silva, N.; Burleson, J. A.; Strausbaugh, L. D.; Gamonal, J.; Diaz, P. I., The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J 2013, 7 (5), 1016-25.
- Lamont, R. J.; Jenkinson, H. F., Subgingival colonization by Porphyromonas gingivalis. Oral microbiology and immunology 2000, 15 (6), 341-9.
- Hajishengallis, G.; Lamont, R. J., Breaking bad: manipulation of the host response by Porphyromonas gingivalis. European journal of immunology 2014, 44 (2), 328-38.
- Nelson, J. W.; Sudarsan, N.; Furukawa, K.; Weinberg, Z.; Wang, J. X.; Breaker, R. R., Riboswitches in eubacteria sense the second messenger c-di-AMP. Nat Chem Biol 2013, 9 (12), 834-9.
- Römling, U.; Galperin, M. Y.; Gomelsky, M., Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 2013, 77 (1), 1-52.
- Wang, P. L.; Oido-Mori, M.; Fujii, T.; Kowashi, Y.; Kikuchi, M.; Suetsugu, Y.; Tanaka, J.; Azuma, Y.; Shinohara, M.; Ohura, K., Heterogeneous expression of Toll-like receptor 4 and downregulation of Toll-like receptor 4 expression on human gingival fibroblasts by Porphyromonas gingivalis lipopolysaccharide. Biochem Biophys Res Commun 2001, 288 (4), 863-7.
- AlQranei, M. S.; Senbanjo, L. T.; Aljohani, H.; Hamza, T.; Chellaiah, M. A., Lipopolysaccharide- TLR-4 Axis regulates Osteoclastogenesis independent of RANKL/RANK signaling. BMC Immunol 2021, 22 (1), 23.
- Bainbridge, B. W.; Coats, S. R.; Darveau, R. P., Porphyromonas gingivalis lipopolysaccharide displays functionally diverse interactions with the innate host defense system. Ann Periodontol 2002, 7 (1), 29-37.
- Darveau, R. P.; Pham, T. T.; Lemley, K.; Reife, R. A.; Bainbridge, B. W.; Coats, S. R.; Howald, W. N.; Way, S. S.; Hajjar, A. M., Porphyromonas gingivalis lipopolysaccharide contains multiple lipid A species that functionally interact with both toll-like receptors 2 and 4. Infect Immun 2004, 72 (9), 5041-51.
- Al-Qutub, M. N.; Braham, P. H.; Karimi-Naser, L. M.; Liu, X.; Genco, C. A.; Darveau, R. P., Hemin-dependent modulation of the lipid A structure of Porphyromonas gingivalis lipopolysaccharide. Infection and immunity 2006, 74 (8), 4474-85.
- Curtis, M. A.; Percival, R. S.; Devine, D.; Darveau, R. P.; Coats, S. R.; Rangarajan, M.; Tarelli, E.; Marsh, P. D., Temperature-dependent modulation of Porphyromonas gingivalis lipid A structure and interaction with the innate host defenses. Infect Immun 2011, 79 (3), 1187-93.
- Olsen, I.; Singhrao, S. K., Importance of heterogeneity in Porhyromonas gingivalislipopolysaccharide lipid A in tissue specific inflammatory signalling. J Oral Microbiol 2018, 10 (1), 1440128.
- Herath, T. D.; Darveau, R. P.; Seneviratne, C. J.; Wang, C. Y.; Wang, Y.; Jin, L., Tetra- and penta-acylated lipid A structures of Porphyromonas gingivalis LPS differentially activate TLR4-mediated NF-κB signal transduction cascade and immuno-inflammatory response in human gingival fibroblasts. PLoS One 2013, 8 (3), e58496.
- Coats, S. R.; Jones, J. W.; Do, C. T.; Braham, P. H.; Bainbridge, B. W.; To, T. T.; Goodlett, D. R.; Ernst, R. K.; Darveau, R. P., Human Toll-like receptor 4 responses to P. gingivalis are regulated by lipid A 1- and 4'-phosphatase activities. Cell Microbiol 2009, 11 (11), 1587-99.
- Matsuura, M., Structural modifications of bacterial lipopolysaccharide that facilitate Gram-Negative bacteria evasion of host innate immunity. Front Immunol 2013, 4, 109.
- Mazgaeen, L.; Gurung, P., Recent advances in lipopolysaccharide recognition systems. Int J Mol Sci 2020, 21 (2).