Herpesviral Infection in Periapical Periodontitis

Abstract

Purpose of Review
This review describes the most recent findings on herpesviral infections and offers current concepts of herpesviral role in the pathogenesis of periapical periodontitis.

Recent Findings
Thirty articles reported data on herpesviral infection in periapical periodontitis. Epstein-Barr virus and human cytomegalovirus are the most frequently detected herpesviruses in periapical samples. The main hypothesis postulates a bidirectional herpesviral-bacterial relationship in the etiopathogenesis of periapical periodontitis. A high heterogeneity of herpesviruses incidence was registered within the studies, in part, due to various methodological approaches used in laboratory testing, different inclusion criteria, study design, seroprevalence of herpesviruses, and sociodemographic characteristics of investigated populations.

Summary
Herpesviruses have been shown to potentially impair local host defense in periapical tissue. Although it has been demonstrated that endodontic pathogenic bacteria are able to reactivate herpesviruses, further, in vitro studies should provide more data on herpesviruses as a factor in the pathogenesis of the periapical pathoses. It is, therefore, necessary to investigate potential benefits of antiviral therapy in well-designed controlled longitudinal studies.

Full text

EPIDEMIOLOGY (M LAINE, SECTION EDITOR)
Herpesviral Infection in Periapical Periodontitis
Aleksandar Jakovljevic
1
&Miroslav Andric
2
&Aleksandra Knezevic
3
&Maja Miletic
1
&Katarina Beljic-Ivanovic
4
&
Jelena Milasin
5
&Mohammad Sabeti
6
Published online: 17 October 2018
#Springer Nature Switzerland AG 2018
Abstract
Purpose of Review This review describes the most recent findings on herpesviral infections and offers current concepts of
herpesviral role in the pathogenesis of periapical periodontitis.
Recent Findings Thirty articles reported data on herpesviral infection in periapical periodontitis. Epstein-Barr virus and human
cytomegalovirus are the most frequently detected herpesviruses in periapical samples. The main hypothesis postulates a bidirec-
tional herpesviral-bacterial relationship in the etiopathogenesis of periapical periodontitis. A high heterogeneity of herpesviruses
incidence was registered within the studies, in part, due to various methodological approaches used in laboratory testing, different
inclusion criteria, study design, seroprevalence of herpesviruses, and sociodemographic characteristics of investigated populations.
Summary Herpesviruses have been shown to potentially impair local host defense in periapical tissue. Although it has been
demonstrated that endodontic pathogenic bacteria are able to reactivate herpesviruses, further, in vitro studies should provide
more data on herpesviruses as a factor in the pathogenesis of the periapical pathoses. It is, therefore, necessary to investigate
potential benefits of antiviral therapy in well-designed controlled longitudinal studies.
Keywords Apical periodontitis .Herpesviruses .Epstein-Barr virus .Human cytomegalovirus .Bone resorption
Introduction
Apical periodontitis is the consequence of host’s immune re-
sponse to necrotic pulp tissue, mostly caused by etiological
agents of endodontic origin [1]. An infected root canal system
is essential for the development of apical periodontitis.
Endodontic infections are characterized by synergistic, antag-
onistic, and commensal interrelationships among resident mi-
croorganisms [2]. Deoxyribonucleic acid (DNA)-based tech-
nologies revealed that over 460 different microbial species/
This article is part of the Topical Collection on Epidemiology
*Aleksandar Jakovljevic
dr.sasuli@hotmail.com; a.jakovljevic@stomf.bg.ac.rs
Miroslav Andric
miroslav.andric@stomf.bg.ac.rs
Aleksandra Knezevic
aknezevic@med.bg.ac.rs
Maja Miletic
maja.miletic@stomf.bg.ac.rs
Katarina Beljic-Ivanovic
katarinabeljicivanovic@yahoo.com
Jelena Milasin
jelena.milasin@stomf.bg.ac.rs
Mohammad Sabeti
Mike.Sabeti@ucsf.edu
1
Department of Pathophysiology, School of Dental Medicine,
University of Belgrade, dr Subotica 1, Belgrade 11000, Serbia
2
Department of Oral Surgery, School of Dental Medicine, University
of Belgrade, dr Subotica 4, Beograd 11000, Serbia
3
Department of Virology, Institute of Microbiology and Immunology,
Faculty of Medicine, University of Belgrade, dr Subotica 1,
Beograd 11000, Serbia
4
Department of Restorative Odontology and Endodontics, School of
Dental Medicine, University of Belgrade, Rankeova 4,
Beograd 11000, Serbia
5
Department of Biology and Human Genetics, School of Dental
Medicine, University of Belgrade, dr Subotica 1, Beograd 11000,
Serbia
6
Department of Endodontics, School of Dentistry, University of
California, San Francisco, CA, USA
Current Oral Health Reports (2018) 5:255–263
https://doi.org/10.1007/s40496-018-0198-7

phylotypes make the current list of endodontic pathogens, in-
cluding bacteria [2], archaea [3], fungi [4], bacteriophages [5],
and other viruses [6••].
Based on the current literature, herpesviral DNA is the
most frequently detected viral DNA in the oral cavity [6••,
7••]. In the last three decades, herpesviruses have been
extensively investigated as potential endodontic pathogens
that are able to induce the development and progression of
apical periodontitis [7••]. Although several hypotheses of
herpesviruses involvement in the pathogenesis of apical
periodontitis have been proposed and generally accepted,
there are still controversies and scientifically unproved
mechanisms that need to be elucidated. Since apical peri-
odontitis is a relatively prevalent condition in general pop-
ulation with potentially significant impact on systemic
health [8], it is important to shed light on unsolved as-
pects of its pathogenesis, including the impact of herpes-
viruses on its development and progression. In an attempt
to understand the proposed roles of herpesviruses in the
pathogenesis of apical periodontitis, this review aimed to
comprehensively outline the current knowledge related to
herpesviral infection in apical periodontitis.
General Aspects of Herpesviruses
There are approximately 120 identified species of herpes-
viruses, of which, eight major types with distinct biologi-
cal and clinical characteristics are known to infect humans.
The eight types include, herpes simplex virus types 1 and
2(HSV1–2), varicella-zoster virus (VZV), Epstein-Barr
virus (EBV), human cytomegalovirus (HCMV), human
herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7),
and human herpesvirus-8 (HHV-8). The prototypical struc-
ture of herpesviruses consists of a double-stranded DNA
genome enclosed within an icosahedral capsid, wrapped in
a tegument, and finally covered by a glycoprotein-bearing
lipid bilayer envelope. Human herpesviruses are further
classified into three subfamilies (α,β,δ). These classifi-
cations are based on tissue tropism, pathogenicity, and
behavior in the laboratory [9,10,11•].
Herpesviridae is derived from the Greek word herpain,
meaning “to creep,”which reflects the feature of those viruses,
namely latent and recurring infection. Herpesviruses are gen-
erally ubiquitous agents that are acquired early in life and
infect individuals from diverse geographical areas and eco-
nomic background. In most individuals, primary infection ex-
hibits few or no overt disease symptoms. After the initial pri-
mary infection, herpesviruses remain in various host cell res-
ervoirs (monocytes, macrophages, lymphocytes, salivary
gland tissue, ductal epithelium of salivary gland tissue, and
sensory nerve ganglia) for the lifetime in a prolonged state of
latency, though the virus retains its capacity to reactivate [12].
Herpesvirus reactivation may occur spontaneously or as a re-
sult of physical and psychosocial stress. Hormonal changes,
infection, immunosuppressive medication, and other events
impairing the host immune defense may also reactivate the
virus [9,10,11•]. Replication of herpesviruses takes place in
the nucleus of the host cell and involves the expression of
immediate-early, early, and late classes of genes. Late
(structural) genes are expressed during the productive (lytic)
phase of herpesvirus infections. Herpesvirus transmission can
occur through intimate contact with infected body fluids,
which include saliva, blood, and genital secretion. Clinical
manifestations of herpesvirus infections are highly diverse
and range from mild or subclinical disease in most systemi-
cally healthy individuals to encephalitis, pneumonia, and oth-
er potentially lethal infections and various types of cancer
including lymphoma, sarcoma, and carcinoma, in immuno-
compromised hosts [9,10,11•].
Evaluation of the Proposed Hypotheses
In 2003, Slots, Sabeti, and Simon proposed a model for
herpesvirus-mediated apical disease [13]. They hypothesized
that herpesviruses may be implicated in the pathogenesis of
apical periodontitis as a direct result of viral infection, viral
replication, or indirectly, as a result of a virally induced impair-
ment of local host defense that favors bacterial overgrowth [13].
The direct cytopathic effects of herpesviruses on periapical
fibroblasts, endothelial cells, and bone cells induce impair-
ment of tissue turnover and repair, ultimately leading to loss
of tissue. It has been reported that fibroblasts infected with
herpesviruses may hamper tissue turnover and repair in regen-
erative periodontal therapy [14]. Additionally, herpesviruses
are able to infect and alter functions of monocytes, macro-
phages, lymphocytes, and polymorphonuclear leukocytes
which lead to significant immunomodulatory and immuno-
suppressive effects at the periapical sites. In this regard,
Ongradi et al. [15] reported the impaired function of neutro-
phils in subjects who carried herpesviruses in oral lympho-
cytes and epithelial cells compared to virus-free individuals.
Indirect mechanisms of herpesviral host impairment include
silencing of natural killer cells, inhibition of apoptosis, de-
struction of components of MHC class I and class II pathways
within macrophages, and disturbance of cytokine and chemo-
kine production. These defensive actions allow them to evade
cytotoxic T cell recognition and natural killer cell lysis
[16–18]. During primary infection, herpesviruses stimulate
the production of various cytokines including TNF-α,
IFN-γ,IL-1β, IL-6, IL-8, IL-10, and IL-12 [19].
Subsequently, Sabeti et al. [20] found significant correlation
between EBV; HCMV infection; and TNF-α,IFN-γ,IL-1β,
and IL-12 in symptomatic periapical lesions. Also, Hernadi
et al. [21] showed increased levels of TNF-αin EBV positive
compared to EBV-negative periapical lesions. Both direct and
256 Curr Oral Health Rep (2018) 5:255–263

indirect activities downregulate the antiviral host immune re-
sponse which leads to persistent herpesviral infection.
According to this hypothesis, the relationship between her-
pesviruses and bacteria is bidirectional and has the characteris-
tics of a vicious cycle. Initially, bacterial virulence factors in
pulp and periodontal tissue have the potential to turn over
herpesviral infection into active stage. Consequently, herpesvi-
rus reactivation induces impairment of local host’s defense
which leads to up growth of resident bacteria in periapical tissue
[13]. It is well known that herpesviral proteins on infected cells
may serve as new attachment sites for bacteria [22], while some
bacterial products may facilitate herpesviral entry into cells and
activate intracellular signaling pathways [23]. Sabeti et al. [24]
showed that Fusobacterium species, Streptococcus species, and
Parvimonas micra were the most common bacterial species in
co-infection with herpesviruses in periapical lesions, while
Verd u go et a l. [25] reported that Tannerella forsythia,
Porphyromonas gingivalis, and Prevotella nigrescens were
the most common bacterial species found in concomitant infec-
tion with EBV. Moreover, in an animal experimental study,
Stern et al. [26] have shown that co-infection of murine CMV
and Porphyromonas gingivalis is characterized by decreased
levels of antiviral IFN-γ.
Sabeti et al. [13] stated that herpesviral-bacterial interac-
tions could explain various clinical characteristics of
periapical infections, including swelling, pain, sensation to
percussion, or palpation. In addition, alternations between
prolonged periods of herpesvirus latency and periods of activ-
ity may partly be responsible for intermittent episodes of ex-
acerbation of periapical disease. Therefore, acute exacerbation
of periapical disease may be due to a combined effect of her-
pesviruses and bacteria [13].
In contrast to the proposed model of herpesviral-bacterial
interaction, Ferreira et al. [27,28] hypothesized that occur-
rence of herpesviruses might be just an epiphenomenon to
bacterial infection that caused inflammation of periapical tis-
sue and consequent influx of virus-infected inflammatory cells
to the periapical area. Those authors argue that the presence of
viral DNA in clinical samples does not necessarily imply a
role in disease pathogenesis [27,28]. Both theories suggest
that virus-infected inflammatory cells, in which herpesviruses
maintained their latency, could be attracted to periapical area.
Histological analyses confirmed that these inflammatory cells
constitute regular infiltrate of periapical granuloma and radic-
ular cysts. Therefore, the essential difference between pro-
posed hypotheses is whether herpesviruses actually may or
may not be reactivated in periapical region and subsequently
induce tissue breakdown.
Detection of Herpesviruses in Apical Periodontitis
The first endeavors to detect herpesviruses in tissue samples of
apical periodontitis lesions were made in the early 1960s of the
past century. Rauch [29] and Shindell [30] in vitro experiments
tried to inoculate monkey kidney cells, HeLa, and human am-
nion cell cultures with potentially virally infected cells of
periapical granulomas. However, due to methodological limi-
tations of their experiments, they could not confirm the pres-
ence of herpesviruses, and they concluded that apical periodon-
titis is probably not associated with a herpesviral infection.
After the development of PCR-based techniques and their
routine use for diagnosis of viral infections, the situation re-
garding herpesviral detection has changed. Namely, by the
mid-1990s Parra, Contreras, and Slots [31,32]detectedsev-
eral viral transcripts in periodontal pockets using PCR. They
concluded that periodontal tissue breakdown occurs more fre-
quently and progresses more rapidly in herpesviral infected
than in herpesviral-free periodontal sites. Based on these re-
sults, they proclaimed herpesviruses as the putative pathogen
in destructive periodontal disease. Shortly after these findings,
Sabeti et al. [33,34] detected herpesviral DNA transcripts in
an apical periodontitis sample also using the PCR method.
The same group [13] stated that concomitant herpesviral in-
fection may contribute to the pathogenesis of apical periodon-
titis in the same way that it was proposed for marginal peri-
odontitis few years ago [31,32].
After these preliminary results, 24 original researches
[34–54,55••,56,57••] investigating different aspects of
herpesviral infection in apical periodontitis were published
in English language. Additionally, the analysis of herpesviral
detection in apical periodontitis has been reported in two sys-
tematic reviews [6••,58], in one narrative review [59••], and in
two book chapters [7••,60••]. Although all eight human her-
pesviruses were analyzed, EBV and HCMV were the most
frequently detected in apical periodontitis samples and healthy
control tissue [6••,7••]. The majority of studies reported that
herpesviruses had occurred significantly more often in apical
periodontitis compared to healthy control tissues [6••,7••].
The detection rates of EBVand HCMV in periapical samples
obviously vary among published studies. Although the major-
ity of studies reported the occurrence of herpesviruses be-
tween 30 to 60% in the examined samples, some of the studies
reported the total absence of herpesviral infection, while on
the other hand; several studies reported 100% presence of the
investigated herpesviruses [6••,7••].
Studies also compared the occurrence of herpesviruses be-
tween apical periodontitis lesions with different clinical, ra-
diographic, and/or histopathological features. Several studies
reported that herpesviral infection is significantly more often
related to symptomatic and large-sized periapical lesions [21,
33,34,45,47,48,53]. On the other hand, several studies did
not report such results [43,49,54,56]. In this regard, the
results of a meta-analysis [6••], which pooled data from six
studies with the same PCR methodology, also suggested that
there was no significant difference in the occurrence of EBV
and HCMV between symptomatic and asymptomatic
Curr Oral Health Rep (2018) 5:255–263 257

periapical lesions. Only four studies investigated the occur-
rence of herpesviruses in apical periodontitis lesions with dif-
ferent histopathological findings [38,40,45,54]. They report-
ed that there were no statistical differences in the occurrence
of herpesviruses between periapical granulomas and radicular
cysts [38,40,45,54].
General Limitations of Conducted Studies:
Methodological Issues
Based on the previously reported data, it is obvious that there
is a discrepancy in the detection rates of herpesviruses in api-
cal periodontitis samples. This is a rather important issue for
the analysis that could be explained by several reasons mainly
related to differences of methodological approach in the con-
ducted studies. The observed differences in these studies have
been extensively reported in a recent systematic review [7••].
Therefore, in this subsection, the authors will highlight and
address the methodological issues which could explain the
cause of such findings.
Replacing classical viral diagnostic techniques, the PCR
method has become the standard methodology for the detection
of herpesvirus nucleic acids. This method has superior technical
performance (high sensitivity, specificity, and speed) and lower
cost advantages over classical techniques (serological, culture-
based, or immunological techniques) [9,10,11•]. When
discussing the use of PCR for the detection of herpesviruses
in apical periodontitis in previous studies, several aspects
should be taken into consideration, including the selection of
the most appropriate PCR method, the selection of primers, the
high sensitivity of this technique, and the possibility of false-
positive and false-negative results [9,10,11•]. In general, single
stage and nested PCR methods are no longer recommended for
routine detection of herpesviruses in apical periodontitis sam-
ples due to high sensitivity (detection of viral copy counts too
low to be of clinical significance) and inability to distinguish
latent episomal viral DNA from genomic viral DNA. On the
other hand, viral activation may be assessed by molecular tech-
niques identifying transcription of genes associated with viral
reactivation or by detecting and determining the number of
nucleic acid copies of infectious agents in a sample. Due to high
seroprevalence of herpesviruses and their clinical significance,
the active viral infection should be tested rather than the latent
one. Therefore, the reverse transcription (RT) and/or quantita-
tive real-time PCR methods (qPCR) are strongly recommended
as a method of choice in herpesviruses detection [9,10,11•].
The sensitivity of PCR techniques is determined by the
selection of primer pairs used in the PCR reaction [60••].
Previous studies reported the use of different primer pairs
targeting different genes for the detection of the same types
of herpesvirus in apical periodontitis samples. For HCMV
detection, the most frequently targeted sequence was for the
HCMV pp65 matrix protein and the immediate-early gene.
Similarly, EBV genome identification by PCR in the analyzed
samples was performed using different targets (EBNA-2,
BLR F2, Bam H1-W fragment etc.) [6••,7••].
Although the majority of conducted studies reported applying
the appropriate laboratory techniques, it is important to be aware
of possible false-negative and false-positive results using the
PCR techniques [9,10,11•]. False-negative PCR results may
be caused by inadequate sampling technique or by inhibitory
effects of components of the amplification process. It can be
avoided by including a non-target DNA sequence as an internal
control in the PCR reaction mixture. In addition, false-positive
results may be caused by cross-contamination among samples or
the contamination of samples by saliva. This can be prevented by
applying good aseptic laboratory practices.
Dissimilar inclusion criteria and inappropriate classifica-
tion of clinical cases in specific subgroups (reversible/irrevers-
ible pulpitis, symptomatic/asymptomatic, and small/large
periapical lesions) are also the reasons for a discrepancy in
the detection rates of herpesviruses in apical periodontitis
samples [6••,7••,9,10,11•]. In previous studies, the partici-
pants were selected consecutively and based on the proposed
inclusion (good general health estimated by the American
Society of Anesthesia, level I or II) and exclusion (probing
depth > 4 mm of involved tooth, with periodontal bone loss,
vertical root fracture, immunocompromised, or patients treat-
ed with antibiotics, antiviral, or immunosuppressive therapy 3
to 6 months before the examination) criteria [6••,7••]. These
criteria should be generally accepted during the selection pro-
cess. Also, the classification of patients in specific subgroups
should be in alignment with the recommendations of
European and/or American endodontic societies [61,62].
Regarding to sampling procedure, all previous studies clear-
ly stated that the collection of samples was performed under
strict aseptic conditions. However, there was discrepancy in the
choice of an appropriate control tissue for the apical periodon-
titis lesions. Although, the healthy pulp tissue has been used as
the counterpart control tissue for the apical periodontitis lesions
in the majority of previous studies [27,28,39,45–48,50,52,
54], few studies reported the use of gingival tissue as control
[13,51]. It must be emphasized that, in the literature, there are
no recommendations about the most appropriate choice, and
further studies are necessary to evaluate the best option.
Other related factors that influence the prevalence of herpes-
viruses are race/ethnicity and socioeconomic status of individ-
uals [63]. Epidemiological results show that as a country be-
comes more developed, the occurrence of herpesviruses may
decrease. Herpesviruses seroprevalence tended to be the highest
in South America, Africa, and Asia and the lowest in Western
Europe and the USA [64,65]. In most of the cases, the results of
previously conducted studies were in accordance with the her-
pesviruses seroprevalence in the USA and Europe [63–65].
Finally, it must be stressed that the study design in all pre-
viously conducted studies was cross-sectional and this
258 Curr Oral Health Rep (2018) 5:255–263

precludes any strong conclusions about the involvement of
identified microbiota as causative agents. As a consequence,
these results may only suggest a possible association between
certain microbial species and disease development, and they
cannot be used for determination of cause-end-effect relation-
ship between them [66]. On the other hand, due to ethical
reasons, prospective longitudinal studies on humans have
not been considered. Hypothetically, more eligible data could
be obtained by an experimental animal model but appropriate
selection of germ-free animals and very strict laboratory con-
ditions for virus manipulation are limiting circumstances.
The Latest Findings Related to Herpesviral Infection
in Apical Periodontitis
As a part of this subsection, we have opted to present the most
interesting findings of three studies [55••,57••,58]reportedin
the last 2 years that deserve significant attention.
Evidence supporting a periodontopathic role of herpesviruses
comes mostly from association studies, but the specific molec-
ular mechanisms by which herpesviruses may cause or exacer-
bate periodontitis are still to be elucidated. Therefore, our re-
search group proposed a mechanism by which EBV infection
induces periapical bone resorption via increased levels of oxi-
dative stress biomarkers and bone resorption regulators (Fig. 1)
[67]. This hypothesis was based on the possibility of EBV to
induce the production of reactive oxygen species (ROS) in spe-
cific cell lines [68] that further stimulated osteoclastogenesis
[69]. We investigated the levels of oxidative stress biomarkers
(8-hydroxydeoxyguanosine (8-OHdG) and oxidized glutathione
(GSSG)), bone resorption regulators (receptor activator of
NF-κB ligand (RANKL), osteoprotegerin (OPG)) in 60 apical
periodontitis lesions and 20 healthy pulp tissues, and then com-
pared the values between 30 EBV-positive and 30 EBV-
negative apical periodontitis lesions [55••]. The presence of vi-
rus was tested by nested and qPCR, while the quantification of
selected parameters was performed by RT-PCR and enzyme-
linked immunosorbent assay (ELISA). It was reported that api-
cal periodontitis samples were characterized by significantly
greater RANKL and OPG mRNA expression, and greater levels
ofGSSGand8-OHdGcomparedtohealthypulptissue.Also,
RANKL and OPG mRNA expression and the imbalance of
RANKL/OPG ratio were significantly higher in EBV-positive
compared to EBV-negative periapical lesions. Although the
levels of GSSG and 8-OHdG were higher in EBV-positive com-
pared to EBV-negative lesions, they did not reach a statistically
significant level. These results were explained by the fact that
EBV was not an isolated pathogen that generated ROS within a
complex system of cells and other microorganisms and their
products in apical periodontitis lesions.
The second study investigated the possibility of
Porphyromonas endodontalis to reactivate latent EBV in vitro
conditions [57••]. Initially, Makino et al. [57••] cloned a pro-
moter region of BamHI fragment Z leftward open reading
frame 1 (BZLF-1) into luciferase expression vectors transfected
into B95-8 BL cells. Then, the luciferase assay was performed
using P. endodontalis culture supernatants or commercially
available n-butyric acid. The authors have reported that after
B-95-8-221 Luc cells were treated with P. endodontalis culture
supernatants or n-butyric acid, the luciferase activity was up-
regulated in a dose-dependent manner. The authors also inves-
tigated BZLF-1 mRNA and BamHI fragment Z EB replication
activator (ZEBRA) protein using qPCR and Western blotting in
Daudi cells (human B-lymphoblastoid cell line established
Fig. 1 Mechanism of periapical
bone resorption enhanced by
Epstein-Barr virus (EBV)
infection. EBV infection in
periapical region induces the
overproduction of reactive
oxygen species (ROS). Increased
levels of ROS stimulated the
excessive production of receptor
activator of nuclear factor kappa-
Βligand (RANKL).
Overexpressed RANKL binds to
its receptor RANK which leads to
osteoclasts differentiation of the
precursor cells and bone
resorption. OPG abbreviation on
Fig. 1denotes osteoprotegerin.
Reprinted from [67]. Copyright
2016, with permission from
Elsevier
Curr Oral Health Rep (2018) 5:255–263 259

from Burkitt lymphoma) after the treatment with
P. endodontalis culture supernatants. They reported that
BZLF-1 mRNA and ZEBRA protein were expressed by
Daudi cells also in a dose-dependent manner. Based on these
findings, they concluded that n-butyric acid produced by
P. endodontalis had reactivated latent EBV in this specific
in vitro model. These results shed light on the previously pro-
posed hypothesis of a herpesviral-bacterial relationship as a
concrete mechanism by which endodontic bacteria could in-
duce the reactivation of herpesviruses in apical periodontitis
cellular milieu [57••].
Finally, the third study is a systematic review related to the
evaluation of potential role of Varicella zoster virus (VZV) and
subsequent Herpes Zoster (HZ) infection in pathogenesis of
periapical pathoses [58]. Although the exact mechanism is not
clearly presented, it was assumed that after VZV reactivation
from trigeminal nerve ganglion virions travel the length of the
nerve to adventitia of dental pulp blood vessels and induce in-
flammation of vasculature adjacent to trigeminal nerve endings.
As a consequence of vasculitis, structural, and functional chang-
es of dental pulp blood vessels occur and induce the develop-
ment of tissue necrosis (Fig. 2)[70,71]. Clinical manifestations
of HZ infection of the head and neck region have been well
documented in the literature and they can range from superficial
skin changes to meningoencephalitis [72]. Since 1975, several
case reports presented unusual cases of apical periodontitis and
root resorption in patients who previously suffered an episode of
HZ attack affecting the mandibular or maxillary trigeminal nerve
branches. All previously published case reports related to this
topic were included in a final systematic review analysis and
authors investigated the level of evidence of VZV contribution
to the development of periapical pathoses. However, in the ma-
jority of included case reports, authors’conclusions that apical
periodontitis and root resorption were the consequence of HZ
infection were based on an association between HZ attack that
happened before and current radiological or clinical findings but
also on the absence of other possible causes of periradicular
inflammation. Therefore, authors concluded that all included
studies had a low level of evidence and that there was a lack of
data that could strengthen the association between VZV infection
and the development of periapical pathoses [58].
Conclusion
Herpesviruses were proposed as putative pathogens in the
development of apical periodontitis. Current hypothesis is re-
lated to the bidirectional relationship between herpesviruses
and endodontic bacteria. However, the specific molecular
mechanisms still have to be elucidated. Although an appropri-
ate germ-free animal model and very strict laboratory condi-
tions for virus manipulation are difficult to attain, further
in vitro studies are expected to provide more data on herpes-
viruses as a factor in the development of periapical pathoses.
In addition, further well-designed controlled longitudinal
studies are necessary to determine whether antiviral therapy
could be beneficial as a novel therapeutic approach in apical
periodontitis treatment.
Acknowledgments The study was supported by grant no. 175075 from
the Ministry of Education, Science and Technological Development of
the Republic of Serbia.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent All reported studies/
experiments with human or animal subjects performed by the authors
have been previously published and complied with all applicable ethical
standards (including the Helsinki Declaration and its amendments,
institutional/national research committee standards, and international/na-
tional/institutional guidelines).
Fig. 2 Mechanism of Varicella zoster virus (VZV)-induced vasculitis of
dental pulp blood vessels. After VZV reactivation from trigeminal nerve
ganglion virions travel the length of the nerve to adventitia of dental pulp
blood vessels. As a consequence of vasculitis, thickening of intima,
paucity of smooth muscle cells, and disrupture of internal elastic lamina
occur. Continuous structural and functional changes of dental pulp blood
vessels induce the development of tissue necrosis and subsequent apical
periodontitis
260 Curr Oral Health Rep (2018) 5:255–263

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