Virulence factors associated with Aggregatibacter actinomycetemcomitans and their role in promoting periodontal diseases

KEYWORDS:

• Aggregatibacter actinomycetemcomitans
• bacterial outer membrane proteins
• cytokines
• periodontal diseases
• virulence factors

This article refers to:

A novel intrinsically disordered outer membrane lipoprotein of Aggregatibacter actinomycetemcomitans binds various cytokines and plays a role in biofilm response to interleukin-1β and interleukin-8

Infectious oral diseases are among the most prevalent in the population worldwide.^1,2 The oral cavity has an extensive and complex composition, with approximately 280 species of bacteria having been isolated and named.³ The microbial populations adhering to the dental structure and the host's defense system are in a dynamic balance; however, this system can receive new colonizations and break the cycle of homeostasis to generate an immune response, resulting in inflammation of the surrounding periodontal tissues.^4-6 Maintenance of the inflammatory response is determined by the presence of a greater proportion of gram-negative bacteria.⁷

The periodontopathogen Aggregatibacter actinomycetemcomitans is a gram-negative bacterium that colonizes the gingival sulcus and invades the epithelial tissues by proapoptotic virulence mechanisms and stimulates the expression of proinflammatory cytokines.⁸ A. actinomycetemcomitans is present in individuals' health conditions in the microbiota, but it can also become the largest colony in cases of aggressive periodontitis, which destroys dental support tissues.⁹ The qualitative and quantitative relation of subgingival biofilm as well as lifestyle and genetic predisposition are factors that help the disease become established. The genetic diversity of A. actinomycetemcomitans isolates has shown the ability to express and release different virulence factors.^10,11 The factors involved in the ability to promote colonization include adhesins, bacteriocins, invasins and antibiotic resistance, which can interact with and adhere to numerous components in the oral cavity.¹² Adhesion is mediated by a wide range of adhesins available in the cell wall, in the form of outer membrane proteins, vesicles, fimbriae or amorphous material.¹³

In this issue, Ahlstrand et al.¹⁴ highlight an outer membrane lipoprotein of A. actinomycetemcomitans, the bacterial interleukin receptor I (BilRl), using mass spectrometry technique and which is specific to the family Pasteurellaceae. In gram-negative bacteria, such as Escherichia coli, the outer membrane serves as a protective barrier that controls the entry and exit of solutes.¹⁰ In addition, it contains other lipopolysaccharides, such as enterobacterial common antigen, and in many conditions a polysaccharide capsule that can be used as an additional layer.¹¹ The outer membrane can anchor organelles and play a fundamental role in the establishment of disease. The illustration (Fig. 1) shows the general structure of a cell wall of gram-negative bacterium characterized by an asymmetrical construction and surrounded by an outer membrane protein located on a fine peptidoglycan layer.¹⁵

Figure 1. The Gram-negative cell wall structure. Adapted from (Silhavy, Kahne and Walker).

Seen in these terms, the remarkable feature found by the authors is the potential of BilRl to bind the proinflammatory cytokine interleukin IL-1ß. In addition, the publication characterizes BilRI as an intrinsically disordered protein (IDP) for its capacity to interact with other ligands and bind different citokynes, such as IL-8, TNF-, INF-γ and IL-10. The mechanism to regulate IDP ensures its production is strict and feasible only in suitable amounts, no more than necessary. The expression has also been associated with numerous diseases.¹⁶ In terms of periodontal disease, little is known about the cytokine sensitization mechanism used by periodontopathogens, and this is important from the point of view that many bacterial species increase their biofilm production and the expression of virulence genes through the mechanism of cytokine binding and sensitization response.¹⁷ The individual humoral immune response mechanism against oral microbiota antigens can occur not only at the local level, but also at the systemic level, bringing with it the risk associated with the development of diabetes and cardiovascular diseases, for example.^4,11 The adaptive immune system in turn attempts to eliminate the pathogens in the late phase of the infection by establishing an immunological memory.⁴ Knowledge of how these inflammatory responses occur is important for understanding complex diseases like periodontitis, particularly the receptors directly involved in binding to bacteria.^11,18 Several pathogens are specific cytokine receptors, and this can result in changes in the properties of the bacteria, altering the biofilm formation, the expression of virulence genes, and they can also change the inflammatory response reactions of the host.¹⁹ Pro-inflammatory cytokines play a key role in the host's response to microbial infections, such as IL-1b and TNF-α, which are essential for the regulation process.^20,21 These same mediators contribute to the induction of bone resorption, signaling an increase in collagenase secretion, the regulation of prostaglandin E2 expression, and they can also be produced by numerous types of cells such as neutrophils, macrophages, natural killer cells, etc. directly in the periodontium.^22,23 Clinical studies have shown a high expression of these markers in patients with periodontal disease.²¹ These cytokines may induce bone resorption, affecting the production of essential osteoclast differentiation and the resulting bone destruction. The stimulatory factors regulating this process are cytokines such as interleukin-1 (IL-1), macrophage colony-stimulating factor (MCSF), monocytes and T cells.^22,24 The treatment of periodontal disease is based on virulence factors, the microorganisms that are established in the processes of health and disease; therefore, the treatments must aim to control these microorganisms.^4,8,9 It is necessary to understand the role of bacterial biofilm in the etiology of periodontal diseases, as the severity and progression of these diseases are determined in large part by factors related to the host's response.^25,26

The results regarding BiIRI are noteworthy because they show what an IDP is and that gene deletion causes a reduction in the internalization of the cytokine IL-1B by the microorganism A. actinomycetemcomitans; an IDP acts as a nonspecific agent that causes the surface concentration. The authors also conclude that in small cytokine concentrations, the role of BiIRI is to promote the entry of molecules onto the surface of the microorganism. The way in which cytokine transfer and protein-binding occur showed a weak affinity, suggesting a possible involvement of BiIRI in the mechanisms that regulate the disease. These findings could also lead in future to a better understanding of the individual functions of bacterial species in the formation of periodontal disease and the mechanisms used by A. actinomycetemcomitans for cytokine sensitization. This study also creates an environment conducive to future investigations involving structural data with molecular dynamics, presenting an ideal situation for a better understanding of how other bacterial species can express cytokine receptors similar to BilRI.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

I am grateful to Dr. Eleftherios Mylonakis, Dr. Thomas J. Silhavy, and the Virulence editorial team for all your support.