Virus Associated Periodontal Diseases: Futuristic
Implications
Amit Parashar1*, Sheetal Sanikop1, Abhishek Zingade1, Shashi Parashar2 and Shikha Gupta3
1Department of Periodontics, KLE VK Institute of Dental Sciences, Belgaum, Karnataka, India
2Division of Virology, Defence R&D Establishment (DRDE), Jhansi Road, Gwalior, MP, India
3Department of Pedodontics, People's Dental Academy, People's University, Bhopal, India
2Division of Virology, Defence R&D Establishment (DRDE), Jhansi Road, Gwalior, MP, India
3Department of Pedodontics, People's Dental Academy, People's University, Bhopal, India
*Corresponding author: Dr. Amit Parashar, MDS, FAGE, FPFA, Department of Periodontics, KLE VK Institute of Dental Sciences, Belgaum, Karnataka
590010, India, Tel: 9685-480-824; Fax: 831-2470-640 E-mail: captamitparashar@gmail.com
Received: August 28, 2014; Accepted: January 06, 2015; Published: January 26, 2015
Citation: Parashar A, Sanikop S, Zingade A, Gupta S, Parashar S (2015) Virus Associated Periodontal Diseases: Futuristic Implications.
J Dent Oral Disord Ther 3(1): 1-5. DOI: http://dx.doi.org/10.15226/jdodt.2015.00133
Abstract
Periodontal diseases have alarmed the current scenario globally.
Still very less evidences has been clued in this area. Previously it was
thought that virus is not involved with severe cases of periodontitis.
In 20th century, virus association of periodontal cases has shown
for the first time. After that several studies covered the strong
evidences about direct virus isolation from deep focal sites. The
articles published recently in journals of repute has shown a very
strong evidences in the involvement of human herpes virus, Epstein
Barr virus, Human cytomegalovirus, Human Immunodeficiency Virus
in both chronic as well aggressive periodontitis. Our main aim of
this review is to have compiled information in this article for what
have been done in the area and remaining futuristic approach; as a
current concern. This will not only help in early diagnostic and virus
characterization as well identification of biomarkers for disease. The
compiled information and critical aspects in the area will also help to
develop suitable diagnostics and therapeutics.
Keywords: Virus; Molecular Methods; Culture; Periodontitis
Keywords: Virus; Molecular Methods; Culture; Periodontitis
Introduction
Periodontal diseases affects millions of people worldwide still
few of them could get proper treatment due to non availability of
actual causing agent for the disease. Oral cavities harbor millions
of unidentified viruses [1,2]. As the research work progressed
periodontitis is now known as the most complex infectious
diseases attribute to multiple viral agents which intern induce
host immune responses. The periodontal disease is a chronic
and degenerative disease that affects and remains localized on
gingiva, periodontal ligament, cementum and alveolar bone.
As the presence of viral strains identified in association of
periodontal diseases a new turning point was observed in this
research area in 21st century [3,4]. But still the progress is very
poor in the area according to available update technologies in
the century. However, not much detailed data is available for
virus involvement and host responses in the pathogenesis of
periodontitis. Detection and quantification of periodontopathic
viral species are useful for identifying subjects at elevated risk
of periodontitis, but do not consistently predict clinical outcome. These uncertainties have given targeted efforts to find viral
etiologic factors for periodontitis.
Individual periodontal lesions harbor millions genomic copies of Human Herpesviruses (HHV), Human Cytomegalovirus (HCMV), Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Human Immunodeficiency Virus (HIV), Hepatitis B And C Virus (HBV, HCV), and Human Enterovirus (HEV). Out of them EBV and CMV are the most commonly researched virus in periodontology and more than 1 million genome copies identified at a single site of infection (Figure 1)[2]. The host immune response attempts to control pathogenic viruses in periodontal sites. However, it is unclear if various immune mediators, such as certain cytokines and chemokines, exert primarily a protective or a destructive role in periodontal disease. Conventionally viruses are much a challenge task for detection and treatment as compared to bacteria. The main bottleneck in this area is to identify the initial stage of the disease and distinguish it properly from initial and late stage. For causing any infection in any host at its particular target sites the conditions proposed to have: Pathogenicity; that is likelihood of causing any disease, Virulence: ability of microorganism to cause any disease (virulent and non-virulent strain), Virulence factors: gene products that enhance potential to establish infection, attachment, evade host immune response, proliferation, damage to host tissue, and transmission (Figure 2 and 3).
Also the adopted survival strategy of the organism in the host environment and favorable selection of microbial species in the environment known as survival of the fittest is also plays a major role in causing viral infections. That is also known as selection pressure coupled with environmental changes. When the equilibrium of host body disturbs it lead to pathology of disease. Due to lack of proper data about infectious and clinical periodontal breakdown that has given rise number of hypothesis about etiology. Few of them have suggested infectious agent like virus is involved with disease mechanism while other emphasize on host immune factor and genetic characteristics.
Major advances in the diagnosis, prevention and treatment
Individual periodontal lesions harbor millions genomic copies of Human Herpesviruses (HHV), Human Cytomegalovirus (HCMV), Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Human Immunodeficiency Virus (HIV), Hepatitis B And C Virus (HBV, HCV), and Human Enterovirus (HEV). Out of them EBV and CMV are the most commonly researched virus in periodontology and more than 1 million genome copies identified at a single site of infection (Figure 1)[2]. The host immune response attempts to control pathogenic viruses in periodontal sites. However, it is unclear if various immune mediators, such as certain cytokines and chemokines, exert primarily a protective or a destructive role in periodontal disease. Conventionally viruses are much a challenge task for detection and treatment as compared to bacteria. The main bottleneck in this area is to identify the initial stage of the disease and distinguish it properly from initial and late stage. For causing any infection in any host at its particular target sites the conditions proposed to have: Pathogenicity; that is likelihood of causing any disease, Virulence: ability of microorganism to cause any disease (virulent and non-virulent strain), Virulence factors: gene products that enhance potential to establish infection, attachment, evade host immune response, proliferation, damage to host tissue, and transmission (Figure 2 and 3).
Also the adopted survival strategy of the organism in the host environment and favorable selection of microbial species in the environment known as survival of the fittest is also plays a major role in causing viral infections. That is also known as selection pressure coupled with environmental changes. When the equilibrium of host body disturbs it lead to pathology of disease. Due to lack of proper data about infectious and clinical periodontal breakdown that has given rise number of hypothesis about etiology. Few of them have suggested infectious agent like virus is involved with disease mechanism while other emphasize on host immune factor and genetic characteristics.
Major advances in the diagnosis, prevention and treatment
Figure 1: Microorganism associated with periodontal diseases
Figure 2: How an organism gets disease after infection.
of periodontitis probably depends upon a better understanding
of the pathogenic infections and the associated host responses.
The main aim behind this review is to decipher precise role of
viruses that may be potentially involved in periodontal disease,
and to evaluate the evidence supporting the hypothesis that viral
infection plays a role in the development of periodontal disease.
Virus presence in periodontal cases
In 21st century new insights into the oral microbial etiology
deciphered the precise role of viruses involved in progression
of periodontal cases. HIV positive patients harbor greater
numbers of HHV in periodontal pockets [5]. HCMV infection also
causes acute infection in a patient infected with HIV was also
deciphered. During childhood, many people acquire primary
infection with HCMV [6-8]. In case of reactivation of these
viruses very chronic infection may occur. Severe disease caused
by HCMV is life-threatening in the HIV infected population [7].
Periodontal occurrences of HHV-6, HHV-7 and HHV-8 have been
reported in HIV seropositive and 14 HIV negative adults (Figure
4) [9,10]. The human periodontium has been investigated for a site of infection or reservoir for HCMV, EBV-1, EBV-2, HSV, HHV-
6 and 7. Human papillomavirus (HPV) is also found associated
with periodontal cases. HPV-16 is detected in oral mucosa; it
was proved through investigation of this virus from periodontal
lesions at disease sites [11-14].
This was also studied well that consequences and disease progression risk is much higher in case of virus and bacterial coinfection in periodontitis. Along with direct involvement of viruses in periodontal cases few medically compromised patients may experience repeated and prolonged HHV re-activation, which may be an important reason for the observed advanced types of periodontitis. However a recent fact is that now we are many steps ahead from assessment of microbiota that could be isolated from lab cultures. As a futuristic and an updated research tool next -generation sequencing technology is required to understand the vast depth of oral viral flora. The huge amount of data obtained from this technique will not only help to make out presence of new viral species but also help to utilize present available diagnostic tools against known viral species like HHV, HIV etc. With the advent of Next-Generation Sequencing (NGS) technologies, researchers were now focusing on in-depth study for profiling of the microbiomes and metagenomes. The integration of bacterial, viral, fungal "metaomes" such as the
This was also studied well that consequences and disease progression risk is much higher in case of virus and bacterial coinfection in periodontitis. Along with direct involvement of viruses in periodontal cases few medically compromised patients may experience repeated and prolonged HHV re-activation, which may be an important reason for the observed advanced types of periodontitis. However a recent fact is that now we are many steps ahead from assessment of microbiota that could be isolated from lab cultures. As a futuristic and an updated research tool next -generation sequencing technology is required to understand the vast depth of oral viral flora. The huge amount of data obtained from this technique will not only help to make out presence of new viral species but also help to utilize present available diagnostic tools against known viral species like HHV, HIV etc. With the advent of Next-Generation Sequencing (NGS) technologies, researchers were now focusing on in-depth study for profiling of the microbiomes and metagenomes. The integration of bacterial, viral, fungal "metaomes" such as the
Figure 3: Generalized mechanism for virus induced periodontal diseases.
Figure 4: Virus induced necrotic ulcers in periodontal case.
meta-transcriptome, meta-proteome, and metametabolome,
together with the host as a major co-factor, should be the ultimate
goal in unraveling the complexity of the oral interactome.
Pathogenesis of virus-associated periodontal disease
HHV has been studied mainly as periodontal disease
pathogenesis model (Figure 5). In the case of HHV it was reported
that after having a lytic cycle viral presence remains in latent
form throughout the life of host. Reactivation of this virus after a
periodic interval may be due to stress or change in host immune
status which may lead to encephalitis, pneumonia, hepatitis and
various form of cancer is a serious concern [15,16]. Periodontal
tissue breakdown occurs more frequently and progress more
rapidly in HHV infected periodontal sites. HHV may cause
periodontal pathology as a direct result of virus infection and
replication, or as a result of virally mediated damage to the host
defense. HHV may exert periodontopathic potential through
at least five mechanisms, operating alone or in combination.
HHV may cause direct cytopathic effects on fibroblasts,
keratinocytes, endothelial cells on inflammatory cells such as
polymorphonuclear leukocytes, lymphocytes, macrophages and
possibly on bone cells, HHV cytopathic effects may hamper tissue
turnover and repair [17-20].
HHV periodontal infections may impair cells involved in host defense, thereby predisposing to microbial superinfection. HCMV and EBV-1 can infect or alter functions of immune cells mainly monocytes, macrophages and lymphocytes [21,22]. Gingival HHV infection may promote subgingival
HHV periodontal infections may impair cells involved in host defense, thereby predisposing to microbial superinfection. HCMV and EBV-1 can infect or alter functions of immune cells mainly monocytes, macrophages and lymphocytes [21,22]. Gingival HHV infection may promote subgingival
Figure 5: Herpes Virus in destructive periodontal disease (Slots, 2005).
attachment and colonization of periodontopathic bacteria,
similar to the enhanced bacterial adherence to virus-infected
cells. The main reason behind it is viral proteins expressed on
eukaryotic cell membranes which act as bacterial receptors
and generate new bacterial binding sites. HHV infections give
rise to altered inflammatory mediator and cytokine responses
[17-20]. Upregulation interleukin 1-beta (IL-1β) and tumor
necrosis factor-alpha (TNF-a) gene expression of monocytes
and macrophages reported in case of HCMV which further lead
to enhanced susceptibility to destructive periodontal disease.
This may also lead to upregulation of matrix metalloproteinase,
downregulation of tissue inhibitors of metalloproteinase and
mediate periodontal bone destruction. HCMV and HHV induce
cell-mediated immunosuppression by reducing the cell surface
expression of MHC (Major Histocompatibility Complex) class I
molecules, thereby interfering with T-lymphocyte recognition. In
addition, HCMV suppress antigen-specific cytotoxic T-lymphocyte
functions, resulting in decreased in circulating CD4+ cells and
increased in CD8+ suppressor cells, which in turn may lead to
global impairment of cell-mediated immunity [23-26].
Virus diagnosis
Virus diagnosis is a challenging task in periodontal cases;
however the revolution in the field of diagnostic made it easy
now a day. Culture of virus in in vitro (cell lines) and in vivo
(animal) model was a gold standard but still a time consuming
method. Rapid diagnosis of virus is essential by using molecular
techniques like PCR, RT-PCR, Real time RT-PCR and sequencing.
Periodontal viruses may be identified successfully by using
diagnostic DNA microarrays that are able to detect simultaneously
HHV, EBV, and CMV. It uses multiplex real-time PCR techniques
to quantify simultaneously the number of genome-copies. HHV,
HCMV and EBV have been isolated from periodontal disease sites
and were confirmed through molecular assays. The presence
of HHV also confirmed through DNA probes, Flow cytometry,
immunofluorescence staining and culture. The human oral cavity
is full of viral species yet to be identified in much detail using
various metagenomics approaches [27-32].
Therapeutic implications
Conventional periodontal therapy can reduce the periodontal
load of viruses. Mechanical debridement may be used to
suppression of subgingival EBV and CMV.
Anti-HHV chemotherapy can also decrease the salivary viral load. A short course of Valacyclovir, 2g twice on the day of treatment and 1g twice the following day, resulted in a significant decrease in the salivary occurrence of EBV. Valacyclovir therapy, 3g per day for 14 days, resulted in a reduction, of more than 100- fold, of Epstein-Barr virus genome-copies in oral wash fluid of patients with acute infectious mononucleosis. Chemotherapeutics are effective against viruses in the lytic phase, but not against viruses in the latent phase, limiting their potential use to diseaseactive infections. Acyclovir types of drugs are acyclic nucleoside analogues that inhibit HHV replication [33-36]. Future management of periodontal diseases may benefit from anti-viral immunotherapy: either prophylactic vaccines, which harness the immune system of healthy subjects to prevent infection with disease-causing viruses; or therapeutic vaccines, which stimulate the immune system into combating existing viruses and disease.
Anti-HHV chemotherapy can also decrease the salivary viral load. A short course of Valacyclovir, 2g twice on the day of treatment and 1g twice the following day, resulted in a significant decrease in the salivary occurrence of EBV. Valacyclovir therapy, 3g per day for 14 days, resulted in a reduction, of more than 100- fold, of Epstein-Barr virus genome-copies in oral wash fluid of patients with acute infectious mononucleosis. Chemotherapeutics are effective against viruses in the lytic phase, but not against viruses in the latent phase, limiting their potential use to diseaseactive infections. Acyclovir types of drugs are acyclic nucleoside analogues that inhibit HHV replication [33-36]. Future management of periodontal diseases may benefit from anti-viral immunotherapy: either prophylactic vaccines, which harness the immune system of healthy subjects to prevent infection with disease-causing viruses; or therapeutic vaccines, which stimulate the immune system into combating existing viruses and disease.
Conclusion
Better understanding of etiology of periodontitis is critical for
developing detection systems and therapies that will enable us
to ensure long lasting disease control [37,38]. This review article
mainly focuses impact of virus associated clinical outcomes
in periodontal cases. Present clues of this pathogenic flora of
periodontium has a futuristic vast area to research on diagnostic
as well as therapeutics. Research during the past 15 years has
implied that numbers of viruses are involved in the etiopathogeny
of destructive periodontal disease. Published literature shows
presence of highly virulent viral species that may lead to severe
infections in form of aggressive and chronic periodontitis. Coinfection
of two viruses like EBV and CMV is also responsible
for progressive periodontitis. HHV also cooperate with specific
bacteria in periodontal tissue breakdown. A co-infection of active
Herpes viruses and periodontopathic bacteria may constitute
a major cause of periodontitis and explain a number of the
clinical characteristics of the disease. The ability of an active
virus infection to alter the periodontal immune responses may
constitute a crucial pathogenetic feature of periodontitis. An
active viral infection can exert direct cytopathogenic effects on key
cells of the periodontium; induce the release of proinflammatory
cytokines [39].
Ongoing research on viral infections of the periodontium has stream lighted towards prevention and treatment of virus induced periodontitis. Studies in the field of virus induced periodontal infections will help in understanding clinical and biological features involved in periodontitis, and also to formulate a new strategies for managing the disease. Detection or quantification of periodontal viruses may prove to have prognostic significance. In order to achieve the final goal to treat any patient up to the maintenance stage so that he/she would be able to get rid of infection truly is at far long. Assessment of the re-activation status of a periodontal infection may help to guide the treatment of patients with severe periodontitis. Development of new vaccines for viruses involved in periodontal disease is required in future which can real hope for low-cost prevention of periodontitis in large groups of individuals. A full understanding of the microbial factors, their pathogenicity as well as host factors are of essential importance for pathogenesis of periodontal disease. In this way it would be possible to treat the periodontal patients adequately.
Therefore to make an effort towards deep understanding regarding etiopathogenesis of disease is required for the development of suitable preventive and therapeutic measures.
Ongoing research on viral infections of the periodontium has stream lighted towards prevention and treatment of virus induced periodontitis. Studies in the field of virus induced periodontal infections will help in understanding clinical and biological features involved in periodontitis, and also to formulate a new strategies for managing the disease. Detection or quantification of periodontal viruses may prove to have prognostic significance. In order to achieve the final goal to treat any patient up to the maintenance stage so that he/she would be able to get rid of infection truly is at far long. Assessment of the re-activation status of a periodontal infection may help to guide the treatment of patients with severe periodontitis. Development of new vaccines for viruses involved in periodontal disease is required in future which can real hope for low-cost prevention of periodontitis in large groups of individuals. A full understanding of the microbial factors, their pathogenicity as well as host factors are of essential importance for pathogenesis of periodontal disease. In this way it would be possible to treat the periodontal patients adequately.
Therefore to make an effort towards deep understanding regarding etiopathogenesis of disease is required for the development of suitable preventive and therapeutic measures.
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