New Viral Facets in Oral Diseases: The EBV Paradox Tonoyan, Lilit; Vincent-Bugnas, Séverine; Olivieri, Charles-Vivien ...
International journal of molecular sciences,
11/2019, Volume:
20, Issue:
23
Journal Article
Peer reviewed
Open access
The oral cavity contributes to overall health, psychosocial well-being and quality of human life. Oral inflammatory diseases represent a major global health problem with significant social and ...economic impact. The development of effective therapies, therefore, requires deeper insights into the etiopathogenesis of oral diseases. Epstein-Barr virus (EBV) infection results in a life-long persistence of the virus in the host and has been associated with numerous oral inflammatory diseases including oral lichen planus (OLP), periodontal disease and Sjogren's syndrome (SS). There is considerable evidence that the EBV infection is a strong risk factor for the development and progression of these conditions, but is EBV a true pathogen? This long-standing EBV paradox yet needs to be solved. This review discusses novel viral aspects of the etiopathogenesis of non-tumorigenic diseases in the oral cavity, in particular, the contribution of EBV in OLP, periodontitis and SS, the tropism of EBV infection, the major players involved in the etiopathogenic mechanisms and emerging contribution of EBV-pathogenic bacteria bidirectional interaction. It also proposes the involvement of EBV-infected plasma cells in the development and progression of oral inflammatory diseases. A new direction for preventing and treating these conditions may focus on controlling pathogenic EBV with anti-herpetic drugs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The periodontal ligament (PDL) is a complex connective tissue that connects the tooth root to the dental alveolar bone and plays crucial mechanical roles. PDL also exhibits regenerative roles and ...regulatory functions to maintain periodontium integrity and homeostasis. While PDL exposure to oral microbial pathogens is common, virtually nothing is known regarding viral infections of PDL. In particular, human herpes simplex virus type 1 (HSV-1) persistently infects the oral cavity through infections of the oral epithelium, connective tissue and neurons. While the oral spread of HSV-1 is generally asymptomatic, this virus has also been implicated in various oral pathologies. In this study, using a primary cell model derived from PDL (PDL cells), and whole surgical fragments of PDL, we provide evidence supporting the efficient infection of PDL by HSV-1 and the promotion of cytopathic effects. Infection of PDL by HSV-1 was also associated with an acute innate inflammatory response, as illustrated by the production of antiviral interferons and pro-inflammatory cytokines. Furthermore, this inflammatory response to HSV-1 was exacerbated in the presence of bacterial-derived products, such as peptidoglycans. This work therefore highlights the ability of HSV-1 to infect mesenchymal cells from PDL, suggesting that PDL may serve as a viral reservoir for the periodontal spread of HSV-1. Moreover, this raises questions about HSV-1 oral pathogenesis, as HSV-1-associated cytopathic and inflammatory effects may contribute to profound alterations of PDL integrity and functioning.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this ...issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone β-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Several subsets of dendritic cells (DCs) are present in the oropharyngeal tonsillar tissues and are thought to behave as major actors in development and regulation of immunity by acting as a first ...line of recognition for airborne and alimentary antigens. We previously discovered in human adult tonsils infected with Epstein-Barr virus (EBV), a subset of DCs that expressed langerin/CD207, a lectin usually recognized as a hallmark of epidermal Langerhans cells (LCs). In the present study, we analyzed the content of several child and adult tonsils in order to characterize in more detail the phenotype of these tonsillar CD207-expressing DCs (tCD207 DCs) and to compare it with that of other human DC subsets. We showed that all the human tonsils studied (n = 12) contained significant proportions of tCD207 DCs among tonsillar cells expressing HLA-DR. Moreover, the presence of tCD207 DCs in tonsils from young children free of EBV infection indicated that these cells could be established early in the tonsil independently of EBV infection. We also showed that tCD207 DCs, that were found mainly located within the tonsillar lymphoid stroma, were distinguishable from LCs by the level of expression of CD1a and EpCAM, and also from human inflammatory DCs by the lack of CD1a, CD206, and CD14 expression. Detailed analysis of cell surface DC markers showed that tCD207 DCs were unrelated to CD141(+) DCs or macrophages, but defined a subtype of tonsillar DCs closely related to myeloid resident CD1c DCs. Since it was established that blood CD1c myeloid DCs exhibit plasticity and are capable of expressing CD207 notably in the presence of inflammatory cytokines, it is tempting to speculate that CD207(+) CD1c(+) DCs may play a specific immune role.
La cavité buccale constitue une porte d’entrée et un site réservoir majeur pour une diversité de virus. Mis à part l’herpèsvirus simplex, peu d’études virologiques détaillent le rôle des virus ...pathogènes de la sphère orale dont le virus d’Epstein-Barr. Le consensus est que les inflammations orales surviennent principalement en réaction à des infections bactériennes et fongiques provoquant une dysbiose du biofilm oral. Toutefois, ce modèle n’est pas parfait et il explique mal les récidives observées après décontamination, le découplage entre dysbiose et poussées inflammatoires, la proximité de dents atteintes et saines dans un environnement bactérien similaire. L’hypothèse d'un mécanisme synergique combinant virus et bactéries a été proposée pour la parodontite. Selon ce modèle, l’action complémentaire des 2 types d’agents infectieux sur le microenvironnement immunitaire favoriserait la chronicité inflammatoire et l’évolution de la maladie. Nos travaux se concentrent sur l’étude de l’infection de la cavité orale par EBV. EBV est un virus ubiquitaire infectant l’homme de manière persistante. La cavité orale est le site privilégié pour sa réplication avec une production salivaire quasi-constante. Outre un rôle transformant majeur, l’implication de EBV est aussi suspectée pour plusieurs maladies inflammatoires. Tout d’abord, nous nous sommes intéressés au lichen plan oral (LPO), une maladie auto-immune dont l'étiopathogénie n’est pas clairement établie. Sur des biopsies de patients atteints de LPO (n=99), nous avons démontré par hybridation in situ que le LPO est fréquemment infecté par EBV (74%), notamment les formes cliniques érosives. Nous montrons que le degré d’infiltration des lésions par des cellules infectées par EBV (EBV+) est corrélé avec les paramètres inflammatoires et que les cellules EBV+ infiltrées sont des plasmocytes. Cela apporte un élément nouveau dans la mesure où les plasmocytes sont reconnus comme des cellules immunitaires régulatrices majeures. Nous décrivons des profils cytokiniques différents entre LPO infectés ou non, sans qu’il soit possible à ce stade de pouvoir impliquer directement les plasmocytes. Nous confirmons par microscopie électronique que les plasmocytes hébergent les stades tardifs du cycle d’EBV et produisent des virions dans le LPO, suggérant un mécanisme d’amplification locale de l'infection. Ensuite, nous nous sommes intéressés à la parodontite, maladie inflammatoire chronique commune qui détruit la structure parodontale et provoque le déchaussement dentaire. Cette maladie est clairement identifiée comme facteur aggravant de nombreuses maladies systémiques. Nos études avaient déjà mis en évidence un lien direct entre infection EBV et la sévérité de la parodontite. Mes travaux ont permis de montrer que le parodonte inflammatoire est infiltré par des cellules EBV+ qui semblent être majoritairement des plasmocytes. La présence de plasmocytes producteurs de virus au sein de la lésion inflammatoire pourrait expliquer l’infection des épithéliums adjacents. De plus, une étude clinique menée sur une petite cohorte de patients traités pour parodontite met en évidence une corrélation entre la diminution de la charge EBV salivaire et l’amélioration clinique de patients après traitement. Si ce résultat se confirme, il constituerait un argument supplémentaire en faveur d’une contribution de l’infection parodontale par EBV à la globalité de la charge EBV salivaire. En conclusion, nos données mettent en évidence la présence quasi constante d’EBV dans deux types de lésions orales inflammatoires. Cette infection virale contribue à aggraver une situation inflammatoire locale associée ou pas à une dysbiose bactérienne. L’observation majeure concerne la présence, souvent massive, de plasmocytes infectés dont le rôle reste à identifier. Ces observations constituent des avancées significatives qui permettent d’étayer un nouveau modèle de pathogénie orale associant virus et bactéries.
The oral cavity is a major entry point and reservoir site for a variety of viruses. Apart from herpesvirus simplex, few virological studies detail the role of oral pathogenic viruses, including Epstein-Barr virus. The consensus is that oral inflammation occurs mainly in response to bacterial and fungal infections causing dysbiosis of the oral biofilm. However, this model is not perfect and does not explain well the recurrences observed after decontamination, the decoupling between dysbiosis and inflammatory outbreaks, the proximity of affected and healthy teeth in a similar bacterial environment. The hypothesis of a synergistic mechanism combining viruses and bacteria has been proposed for periodontitis. According to this model, the complementary action of the 2 types of infectious agents on the immune microenvironment would promote inflammatory chronicity and disease progression. Our work focuses on the study of oral cavity infection with EBV. EBV is a ubiquitous virus that persistently infects humans. The oral cavity is the preferred site for its replication with almost constant saliva production. In addition to a major transformative role, EBV's involvement is also suspected for several inflammatory diseases. First, we focused on oral plan lichen (OPL), an autoimmune disease whose etiopathogeny is not clearly established. On biopsies of patients with OPL (n=99), we demonstrated by in situ hybridization that OPL is frequently infected with EBV (74%), particularly in erosive clinical forms. We show that the degree of infiltration of lesions by EBV-infected cells (EBV+) is correlated with inflammatory parameters and that the infiltrated EBV+ cells are plasma cells. This brings a new element to the extent that plasma cells are recognized as major regulatory immune cells. We describe different cytokinic profiles between infected and uninfected OPL, although it is not possible at this stage to directly involve plasma cells. We confirm by electron microscopy that plasma cells host the late stages of the EBV cycle and produce virions in the OPL, suggesting a local amplification mechanism of infection. Then, we focused on periodontitis, a common chronic inflammatory disease that destroys the periodontal structure and causes tooth loosening. This disease is clearly identified as an aggravating factor in many systemic diseases. Our studies had already shown a direct link between EBV infection and the severity of periodontitis. My work has shown that the inflammatory periodontium is infiltrated by EBV+ cells, which appear to be predominantly plasma cells. The presence of virus-producing plasma cells within the inflammatory lesion may explain the infection of adjacent epithelia. In addition, a clinical study conducted on a small cohort of patients treated for periodontitis showed a correlation between the decrease in salivary EBV load and the clinical improvement of patients after treatment. If this result is confirmed, it would be an additional argument in favour of a contribution of periodontal EBV infection to the overall salivary EBV burden. In conclusion, our data show the almost constant presence of EBV in two types of inflammatory oral lesions. This viral infection contributes to worsening a local inflammatory situation associated or not with bacterial dysbiosis. The main observation concerns the presence, often massive, of infected plasma cells whose role remains to be identified. These observations represent significant advances that support a new model of oral pathogenesis combining viruses and bacteria.
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