type of virus n role in periodontal disease

1. ROLE OF VIRUSES IN
PERIODONTAL DISEASES
Presented by:
Dr Ripunjay kr Tripathi
Post Graduate Student
Dept of Periodontology

2. INTRODUCTION
 A virus is a small infectious agent that can
replicate only inside the living cells of an
organism.
 Viruses can infect all types of organisms,
from animals and plants to bacteria and archaea.
 The study of viruses is known as virology, a sub-
speciality of microbiology.
 The word is from the Latin virus referring
to poison and other noxious substances, first
used in English in 1392.

3. INTRODUCTION
 Dmitri Ivanovsky in 1892 described a non-bacterial
pathogen infecting tobacco plants.
 Tobacco mosaic virus – first plant virus was
descirbed by Martinus Beijerinck in 1898. He called the
virus particles contagium vivum fluidum (soluble living
germ) and re-introduced the word virus.
 In the same year Friedrich Loeffler and Frosch passed
the first animal virus – agent of foot-and-mouth
disease (aphthovirus).
 In the early 20th century, the English
bacteriologist Frederick Twort discovered a group of
viruses that infect bacteria, now called bacteriophages

4. STRUCTURE OF VIRUSES

5. Examples of medically important
virus families
DNA, double-stranded, enveloped
viruses
Herpesviridae Herpes simplex virus 1 and 2,
varicella-zoster virus,
Epstein-Barr virus,
cytomegalovirus, herpesvirus 8
(Kaposi’s sarcoma virus)
Hepadnaviridae Hepatitis B virus
Poxviridae Smallpox virus (variola)
DNA, double-stranded, naked
viruses
Papovaviridae Papillomaviruses (warts)

6. RNA, double-
stranded,
enveloped
viruses
Retroviridae Human immunodeficiency virus (HIV), human T-cell
lymphotropic virus
Orthomyxoviridae Influenza virus type A, B and C
Paramyxoviridae Mumps virus, measles virus
Coronaviridae Severe acute respiratory syndrome (SARS)
Flaviviridae Hepatitis C virus, yellow fever virus
Togaviridae Rubella virus
Rhabdoviridae Rabies virus
Filoviridae Ebola virus

7. RNA, double-stranded, naked
viruses
Reoviridae Rotavirus gastroenteritis (infantile
diarrhea)
RNA, single-stranded, naked
viruses
Picornaviridae Polioviruses, Coxsackie viruses,
hepatitis A virus
Caliciviridae
Hepatitis E virus, Norwalk group
of gastroenteritis viruses

8. Characteristics of
enveloped and naked
viruses
Property Enveloped viruses Naked viruses
Surface structure Lipid-protein
membrane
Proteins
Virion stability Environmentally labile Environmentally stable
Virion release Budding or cell lysis cell lysis
Virion transmissibility Must stay wet Readily
Predominant immunity Cell-mediated
response
Antibody response
Vaccine development Complicated Relatively easy

9. ORAL VIRAL INFECTIONS OF
ADULTS
JØRGEN SLOTS

10. Virus Viral
genom
e
Envelop
ed
virus
Characteris
tics
Disease association
Herpes
viruses
Double-
strande
d
DNA
Yes
Herpes
simple
x
virus-1
Latency in
sensory
ganglia.
Causes
Orolabial
Disease.
Herpetic gingivostomatitis,
recurrent orolabial
lesions, herpetic
Whitlow,
Kerato conjunctivitis,
Pharyngitis

11. Virus Viral
genome
Envel
oped
virus
Characteristics Disease association
Herpes
simplex
virus-2
Latency in
sensory
ganglia. Causes
genital
and newborn
infections
Genital infection, aseptic
meningitis
Varicella–
zoster
virus
Latency in
sensory
ganglia. Only
three
major genotypes
of the
wild-type virus are
known. More than
90%
are infected
before
adolescence in an
unvaccinated
population
Varicella (chickenpox),
herpes zoster (shingles),

12. Epstein–
Barr
virus
Identified initially in
1964 from African
Burkitt lymphoma.
Infects epithelial cells
with a cytolytic
infection
and B lymphocytes
with a latent infection
Infectious mononucleosis,
hairy leukoplakia of the
tongue, Burkitt lymphoma,
Hodgkins Lymphoma
Human
Cytomeg
alovirus
Infects mainly T
lymphocytes and
macrophages.
Preterm birth, preeclampsia,
Transplant rejection,
hemorrhagic retinal
necrosis (HIV patients),
pneumonia and
encephalitis

13. Human
herpesvirus-
6
Cell tropism for T
lymphocytes and
neural
cells. Frequently shed
in the saliva of
healthy
donors
Roseola infantum (sixth
disease), meningitis,
encephalitis, possibly
multiple sclerosis
Human
herpesvirus-7
Latency in
macrophages
and T lymphocytes.
Frequently shed in the
saliva of healthy donors
Exanthema subitum,
macular-papular rashes,
transplant-recipient
pathogen
Human
herpesvirus-8
B lymphocytes and
monocytes serve as
reservoirs
Kaposis sarcoma, primary effusion
lymphoma, mononucleosis-like
illness,
aplastic anemia.
Unlike the Epstein-Barr virus,
herpesvirus- 8 is not involved in
epithelial tumors

14. Virus Viral
genome
Enveloped
virus
Characteristics Disease association
Papillomavirus
es
Double-
stranded
DNA
No Epithelial cell
proliferation with
specificity principally in
the ano-genital area,
urethra, skin, larynx,
tracheo-bronchial and
oral mucosa.
Genital and cutaneous
warts, cervical and
anogenital
Cancers
Picornaviruses Single-
stranded
RNA
No
Coxsackievirus Coxsackie virus A16 is
closely related to
Enterovirus-71, and both
belong to a discrete
subgroup of type A
enteroviruses that are
prominently associated
with hand, foot and
mouth diseas
Uncomplicated hand, foot
and mouth disease
(Coxsackie virus A
serotypes 10 and 16),
Herpangina (mostly
Coxsackie virus A),
Myocarditis,
Infectious type 1 diabetes
(Coxsackie virus B),
Atherosclerosis

15. Virus Viral
genome
Envel
oped
virus
Characteristics Disease association
Echovirus Some echovirus
replication occurs in the
nasopharynx
Meningitis, pericarditis,
myocarditis, herpangina,
Guillain-Barre´ syndrome
Enterovirus Enterovirus-71 was first
isolated in 1969 from a
child with encephalitis.
Can cause large epidemics
of acute disease. Mutates
readily
Hand, foot and mouth
disease (enterovirus-71),
herpangina (enterovirus-
71),
poliomyelitis-like illness,
meningoencephalitis
(enterovirus-71)

16. Virus Viral
Genome
Enveloped
virus
Characteristics Disease association
Retrovir
uses
Single-
stranded
RNA
Yes
Human
immuno
deficienc
y
virus-1
Global infection;
infects cells
containing CD4
receptor, such as
T-helper
lymphocytes and
cells of the
macrophage lineage
The rank order of
AIDS-defining
pathoses is as
follows:
Pneumocystis
pneumonia (43%),
esophageal
candidiasis (15%),
Kaposis sarcoma
(11%), disseminated
Mycobacterium
avium
infection (5%),
Mycobacterium
tuberculosis (5%),
cytomegalovirus
disease (4%),
HIV-associated
dementia (4%),
recurrent bacterial
pneumonia (3%)
and toxoplasmosis
(3%)

17. Virus Viral
Genome
Enve
lope
d
virus
Characteristics Disease
association
Human
immunodeficienc
y
virus-2
Infection
occurring
mainly in
West-Central
Africa
(Guinea
Bissau)
HIV-2 is
associated
with similar
types of
diseases as
HIV-1,
but is generally
less
virulent

18. ORAL VIRAL INFECTIONS OF
CHILDREN
MATTI SA¨ LLBERG
Viruses causing pathosis in the oral cavity of children
 Enteroviruses
 Morbilli virus (measles)
 Mumps virus
 Herpes simplex virus-1 and aphthous ulcers
 Epstein–Barr virus
 Human papillomavirus
Viruses indirectly causing pathosis or which can be
transmitted through dental treatments
 Human immunodeficiency virus type 1
 Hepatitis B virus
 Hepatitis C virus

19. HUMAN VIRUSES IN
PERIODONTITIS
Slots

20. Need to find additional etiologic
factors for periodontitis:
 Periodontitis - attributable to multiple infectious agents
and interconnected cellular and humoral host immune
responses
 Precise role of various putative pathogens and host
responses in the pathogenesis of periodontitis – still
unclear.
 In hosts with comparable levels of risk factors, some
periodontal infections result in loss of periodontal
attachment and alveolar bone while other infections are
limited to inflammation of the gingiva with little or no
discernible clinical consequences.
 Also, many periodontitis patients do not show a
remarkable level of classical risk factors.

21. Periodontal health and gingivitis
 Periodontal health is associated with median
genome detection rates of 8% for Epstein–
Barr virus and cytomegalovirus .
 Healthy peri-implant sites have demonstrated
an absence of cytomegalovirus. (Nowzari H, Botero JE,
DeGiacomo M, Villacres MC, Rich Clin Implant Dent Relat Res 2008)
 Gingivitis studies reveal a median genome
detection rate of 20% for Epstein– Barr virus
and 33% for cytomegalovirus.

22. Aggressive periodontitis
 Cytomegalovirus and Porphyromonas
gingivalis act synergistically to influence
the risk for both the occurrence and the
extent of disease.
 Chances of having localized aggressive
periodontitis increased multiplicatively in
individuals with a co-infection of
cytomegalovirus and P.
gingivalis,compared with the odds of
harboring neither of the two infectious
agents

23. Prevalence of subgingival
genome-copies of herpesviruses
in aggressive periodontitis
 Median detection rates for:
 HSV1- 78%
 EBV – 58%
 CMV – 42%

24. Herpesviruses in Localized
juvenile periodontitis
Ting M, Contreras A, Slots J: Herpesviruses in localized juvenile periodontitis.
J Periodont Res 2000
 HCMV, EBV-1 and HSV were detected
more frequently in deep periodontal
pockets than in shallow periodontal sites
of LJP patients.
 Using similar detection methods, HCMV
or EBV-1were detected in 90% of LJP
lesions but only in 40-78% of adult
periodontitis lesions

25.  Active HCMV infection was
demonstrated in LJP lesions of 5 HCMV-
infected subjects aged 10- 14 yr.
 In contrast, HCMV activation was not
demonstrated in shallow periodontal
sites in the same 5 patients and in the
healthy 7-yr-old girl.
 Latent HCMV infection was also
detected in 2 of the 3 older LJP patients,
who presumably exhibited slowly or non-
progressing disease.

26. Pathogenesis of localised
aggressive periodontitis
 Ting et al hypothesis –
primary CMV infection at the time of
root formation of permanent incisors
and first molars (3-5 years of age)
can disrupt normal cell differentiation ,
change the morphology of developing
teeth (cemental hypoplasia)
giving rise to a defective
periodontium.

27. Pathogenesis of localised
aggressive periodontitis
hormonal changes at the
onset of puberty
in suppression of
antibacterial immune
defenses
overgrowth of bacteria,
such as specific
genotypes of A.
actinomycetemcomitans,
may re-activate a
periodontal
cytomegalovirus infection

28. Pathogenesis of localised
aggressive periodontitis
 LAP lesions harbouring an active CMV infection tend to be
more heavily infected with A. actinomycetemcomitans than
sites showing a latent CMV infection.
 The affinity of A. actinomycetemcomitans for colonizing CMV
-infected epithelial cells may partly explain the close
association of the organism with the disease.
 Also, A. actinomycetemcomitans may be able to inhibit
epithelial cell proliferation by means of a cytolethal distending
toxin .
 CMV -mediated damage to the periodontal tissue
constituents, antiviral proinflammatory cytokine responses,
and bacteria-induced injury of the epithelium, may allow
gingival tissue invasion by A. actinomycetemcomitans and
breakdown of the periodontal attachment and alveolar bone

29. Chronic periodontitis
 Hochman et al. detected antibodies against
Epstein–Barr virus in 32%, and against
cytomegalovirus in 71%, of gingival crevice
fluid samples from 34 study sites.
 Antibodies against the herpesviruses were
predominantly of the immunoglobulin A (IgA)
isotype in the gingival crevice fluid and of the
immunoglobulin G (IgG) isotype in serum
samples.
 These antibody findings suggest a local
synthesis by plasma cells.

30. Prevalence of subgingival
genome-copies of herpesviruses
in chronic periodontitis
 Median detection rates for:
 HSV 1- 26%
 EBV – 46%
 CMV – 52%

31.  The Epstein–Barr virus nuclear
antigen 2 (EBNA2) genotype 1 occurs
more frequently in periodontitis lesions
than the EBNA2 genotype 2.
 Periodontitis lesions can also harbor
papillomaviruses, human
immunodeficiency virus (HIV), human
T-lymphotropic virus type 1, hepatitis
B virus, hepatitis C virus.

32. Review of literature
 Sunde, P. T., Olsen, I., Enersen, M., Beiske,
K. and Grinde, B. (2008), (Journal of Medical
Virology)
 Of the apical periodontitis samples, 50%
contained EBV, while none contained HCMV.
Of the marginal periodontitis samples, 40%
were positive for EBV and 12% for HCMV.
Significant associations were found between
periodontal EBV and the presence
of Aggregatibacter
actinomycetemcomitans andPorphyromonas
gingivalis.

33.  Şahin, S., Saygun, I., Kubar, A. and
Slots, J. (2009), (Oral Microbiology
and Immunology)
 HCMV and EBV are commonly
present in the saliva of periodontitis
patients. Periodontitis lesions of
systemically healthy subjects seem
to constitute the main origin of
salivary HCMV, but do not comprise
the sole source of salivary EBV.

34. Periodontal abscess
 Bacteria typically recovered from periodontal abscesses are
Fusobacterium spp. (75% of abscesses studied),
Prevotella intermedia ⁄ nigrescens (60%),
P. gingivalis (51%) and
A. actinomycetemcomitans(30%).
(Jaramillo A, Arce RM, Herrera D, Betancourth M, Botero JE,
Contreras A . J Clin Periodontol 2005: 32)
 Epstein–Barr virus was detected in 72%, cytomegalovirus in 67%,
and co-infection with the two viruses in 56% of 18 abscesses
studied, and the herpesviruses were not identified in healthy
periodontium or after treatment of the periodontal abscess.
(Saygun I, Yapar M, O¨ zdemir A, Kubar A, Slots J. Oral Microbiol
Immunol 2004: 19)
 It is suggested that re-activation of a periodontal herpesvirus latent
infection impairs the periodontal host defense, which permits
bacterial pathogens to enter the gingiva and cause abscess
formation.

35. Periodontal diseases in
compromised subjects
HIV-associated periodontitis
 Cytomegalovirus infection in neonates and immuno
compromised patients (HIV-infected patients and transplant
recipients) has a high rate of morbidity.
 HIV-induced immunosuppression facilitates herpes virus re-
activation, but active herpes viruses may also activate latent
HIV .
 Re-activation of latent periodontal herpes viruses by HIV
may start a cascade of tissue-destructive events leading to
periodontal breakdown.
 Periodontitis in HIV-infected patients may resemble
periodontitis of non HIV-infected individuals, or be associated
with profuse gingival bleeding or necrotizing gingival tissue.

36.  Cytomegalovirus was identified in 81% of HIV
associated periodontitis lesions and in 50% of
non- HIV-associated periodontitis lesions,
and was the most common herpesvirus
identified.
 In HIVinfected individuals, cytomegalovirus
has also been implicated in acute
periodontitis , in periodontal abscess
formation, in mandbular osteomyelitis and in
refractory chronic sinusitis.
 Herpesvirus-like virions were detected
electronmicroscopically in 56% of gingival
tissue from HIV-seropositive patients with
necrotizing ulcerative periodontitis.

37.  Epstein–Barr virus type 1 was identified more frequently
in subgingival sites of HIV-positive patients than in
subgingival sites of HIV-negative patients. Epstein–Barr
virus type 2, which is frequently found in HIV-infected
subjects, was detected in 57% of biopsies from HIV-
associated periodontitis lesions, but was absent in non-
HIV associated periodontitis biopsies.
 Human herpesvirus- 8 was present in periodontitis
lesions of 24% of HIV-infected individuals with no
clinical signs of Kaposi's sarcoma, but was not
recovered from periodontitis sites of non-HIV-infected
individuals.
 Herpes simplex virus, Epstein–Barr virus,
cytomegalovirus and human herpesvirus-8 genomes
occur frequently in the saliva of HIV-infected individuals,
and have been related to ulcerative oral lesions,
widespread gingival and mucosal inflammation, and
oral cancer.

38. Necrotizing ulcerative
gingivitis ⁄ periodontitis
 Necrotizing ulcerative gingivitis ⁄ periodontitis affects
immunocompromised, malnourished and psychosocially
stressed individuals.
 In developing countries, necrotizing gingivitis may expand
considerably beyond the periodontium and give rise to the life
threatening disease termed noma or cancrum oris.
 Noma affects primarily children and is sometimes preceded by a
viral infection, such as herpetic gingivostomatitis or measles, or
HIV, which may impair host defenses against resident viruses
and pathogenic bacteria.
 Contreras et al. studied necrotizing ulcerative gingivitis in
nonHIV-infected malnourished Nigerian children, 3–14 years of
age.
 Necrotizing gingivitis lesions of malnourished children yielded
herpes simplex virus (23% of study lesions), Epstein–Barr virus
(27%) and cytomegalovirus (59%), whereas periodontal sites of
malnourished, but periodontally normal children revealed

39. Human herpesviruses in
periodontitis associated with
syndromes
Disease Periodontal viruses
Guillain–Barre´ syndrome Cytomegalovirus
Kostmann syndrome Epstein–Barr virus
Fanconi_s anemia Herpes simplex virus,
Cytomegalovirus
Papillon–Lefe`vre syndrome Epstein–Barr virus,
cytomegalovirus
Down syndrome Herpes simplex virus (26%),
Epstein–Barr virus type 1
(37%), cytomegalovirus (37%)

40. Oral diseases
 In the oral cavity, periodontitis has been associated with papillomavirus-16-related
squamous cell carcinoma of the tongue
 Co-infection with papillomavirus-18 and Epstein–Barr virus has also been linked
to tongue carcinoma.
 As periodontitis lesions frequently harbor papillomaviruses, and may even
comprise the major oral reservoir of the virus, periodontitis sites in intimate contact
with the tongue may serve as the source of oncogenic papillomaviruses.
 A similar hypothesis proposes that periodontitis lesions supply Epstein–Barr virus
for the development of hairy leukoplakia of the tongue.
 Papillomaviruses have also been associated with the potentially malignant
disorders of oral leukoplakia and oral lichen planus.
 Cytomegalovirus may play a role in the development of the non-neoplastic
peripheral giant cell granuloma around teeth.
 Studies are needed to determine if the treatment of periodontal viral infections
can decrease the incidence of oral tumors

41. HERPESVIRUSES IN
PERIODONTAL DISEASES
Jørgen Slots

42. HERPESVIRUS
 STRUCTURE
 Membership in the family Herpesviridae is
based on a four-layered structure of the
virion.
 Herpesviruses have
(i) a core containing a large double stranded
DNA genome encased within
(ii) an isosapentahedral capsid containing 162
capsomers,
(iii) An amorphous proteinaceous tegument
and,
(iv) surrounding the capsid and tegument, a
lipid bilayer envelope derived from host cell
membranes

43. Herpesvirus virion.

44. Human herpesviruses
Herpesviruses Herpes
group
Herpes simplex virus type 1
HSV-1
alpha
Herpes simplex virus type 2
HSV-2
alpha
Varicella-zoster virus
VZV
alpha
Epstein-Barr virus
EBV
gamma
Human cytomegalovirus
HCMV
beta
Human herpesvirus 6
HHV-6
beta
Human herpesvirus 7
HHV-7
beta
Human herpesvirus 8
HHV-8
gamma

45.  Alpha-herpesviruses are neurotropic,
have a rapid replication cycle, and
display a broad host and cell range.
 The beta and gamma herpesviruses
differ in genomic size and structure,
but replicate relatively slowly and in a
restricted range of cells, mainly of
lymphatic or glandular origin.

46. Type Primary
target cell
Oral affection Other pathology
1. HSV -
1
Mucoepithelial Herpes ulcers Genital ulcers
2. HSV- 2 Mucoepithelial Herpes ulcers Genital ulcers
3. VZV Mucoepithelial Possible oral
manifestations of
chicken pox and
herpes zoster
Chicken pox, herpes zoster
4. EBV B-cells and
epithelial cells
Hairy leukoplakia,
periodontitis,
(nasopharyngeal
carcinoma)
Mononucleosis, lymphoma
5. CMV Monocytes,
lymphocytes
and
epithelial cells
Periodontitis? Mononucleosis

47. Type Primary target cell Oral
affection
Other pathology
6. HHV - 6 T-cells and possibly
others
Roseola in infants
7. HHV - 7 T-cells and possibly
others
Roseola in infants
8. HHV –
8
Probably lymphocytes
and
epithelial cells
Kaposi’s sarcoma (in AIDS
patients)

48. Life Cycle
 Viral infection can lead either to a rapid
replication of the agent and destruction of the
infected cell, or to a prolonged period of
latency.
 DNA viruses (except poxviruses) replicate in
the nucleus and are more likely to persist in
the host, whereas RNA viruses (except
retroviruses) replicate in the cytoplasm.
 Latency/ persistence is maintained for EBV in
resting memory B lymphocytes, and for
HCMV in dendritic cells and in monocytes
and their progenitors.

49. virion particle recognizies and attaches to
surface receptors of the mammalian cell
viral penetration into the cell
transcription of viral mRNA, viral protein
synthesis, and replication of the viral genome
viral genome and structural proteins
assembled
virions are released from the cell by
exocytosis or by cell lysis.

50. Association between
herpesviruses and periodontal
disease
 Sabiston suggested an association
between HCMV and periodontal disease.
 In inflammatory cells of juvenile
periodontitis gingival biopsy specimens;
Burghelea & Serb described the
presence of nuclear body-type structures
and virus-like inclusions which,
considering recent findings by Ting et al.,
might have been herpesviruses.

51.  In adult periodontitis lesions, HSV infects T-lymphocytes and
monocytes/macrophages , HCMV infects periodontal
monocytes ⁄ macrophages and T-lymphocytes, and EBV
infects periodontal B-lymphocytes.
 Herpesvirus-infected inflammatory cells elicit tissue-
destroying cytokines and may exert diminished ability to
defend against bacterial challenge.
 Herpesvirus- associated periodontal sites also tend to
harbour elevated levels of periodontopathic bacteria,
including Porphyromonas gingivalis, Tannerella forsythia,
Dialister pneumosintes ⁄ Dialister invisus, Prevotella
intermedia, Prevotella nigrescens, Treponema denticola,
Campylobacter rectus and Actinobacillus
actinomycetemcomitans.
 Understanding the pathobiology of periodontal herpesviruses
may help delineate molecular determinants that cause
gingivitis to progress to periodontitis or stable periodontitis to
convert to progressive disease.

52.  Herpesviruses may also interfere with
periodontal healing. In guided tissue
regeneration, Smith MacDonald et al.
found that 4 periodontal sites showing
either EBV-1 or HCMV had an average
gain in clinical attachment of 2.3 mm
compared with 16 virally negative sites
that showed a mean clinical attachment
gain of 5.0 mm (p~0.004).
 By infecting and altering functions of
fibroblasts, Herpesviruses may reduce
the regenerating potential of the
periodontal ligament.

53. Pathogenesis of herpesvirus-
associated periodontal
disease
 Herpesviruses 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.
 Herpesviruses may exert
periodontopathic potential through at
least 5 mechanisms, operating alone
or in combination.

54.  1. Herpesviruses may cause direct cytopathic effects on
fibroblasts, keratinocytes, endothelial cells, on inflammatory
cells such as polymorphonuclear leukocytes,lymphocytes,
macrophages , and possibly on bone cells. Since the above
cells are key constituents of inflamed periodontal tissue,
herpesvirus-induced cytopathic effects may hamper tissue
turnover and repair.
 2. Herpesviral periodontal infections may impair cells involved
in host defense, thereby predisposing to microbial
superinfection. HCMV and EBV-1 can infect and/or alter
functions of monocytes, macrophages and lymphocytes.
 3. Gingival herpesvirus infection may promote subgingival
attachment and colonization of periodontopathic bacteria,
similar to the enhanced bacterial adherence to virus-infected
cells observed in medical infections, Viral proteins can act as
bacterial receptors and generate new bacterial binding sites.
Loss of virus-damaged epithelial cells can expose the
basement membrane and the surface of regenerating cells,
providing new sites for bacterial binding.

55. 4. Herpesviral infections can give rise to altered inflammatory
mediator and cytokine responses.
 HCMV infection can upregulate interleukin 1-beta (IL- 1b) and
tumor necrosis factor-alpha (TNF-a) gene expression of
monocytes and macrophages. Increased production of the
proinflammatory cytokines IL-1b and TNF-a by macrophages
and monocytes has been associated with enhanced
susceptibility to destructive periodontal disease.
 In turn, IL-1b and TNF-a may up-regulate matrix
metalloproteinase, downregulate tissue inhibitors of
metalloproteinase and mediate periodontal bone destruction.

56.  EBV and other members of the Herpesviridae family
elaborate compounds that may exert important regulatory
effects on host cell cytokine synthesis.
 EBV-encoded protein BCRF1 possesses a striking structural
and functional similarity with IL-10, which can suppress TH1
cell-mediated IL-2, interferon-c and lymphotoxin production
and polarize the immune system toward a TH2-type
response, TH1-type response has been associated with
protection against perioodntitis whereas TH2- type seems to
be related to progressive periodontal disease.
 In addition, EBV infection of B lymphocytes can induce a shift
in lymphocyte subpopulations toward predominance of
Blymphocytes/ plasma cells. EBV-mediated transformation of
B-lymphocytes to plasma cells may occur in periodontal
disease as evidenced by a B-lymphocyte dominance and
polyclonal B lymphocyte activation in periodontitis lesions. B
lymphocytes/ plasma cells are particularly prominent in
progressive periodontitis lesions.

57. 5. HCMV and HSV can induce cell-mediated immune
suppression by reducing the cell surface expression of
MHC (major histocompatibility complex) class I
molecules, thereby interfering with T-lymphocyte
recognition.
 HCMV can cause metabolic abnormalities in
lymphocytes and monocytes.
 In addition, HCMV can suppress antigen-specific
cytotoxic T-lymphocyte functions, resulting in decreases
in circulating CD4+ cells and increases in CD8+
suppressor cells, which in turn may lead to global
impairment of cell-mediated immunity.
 EBV may trigger a proliferation of cytotoxic T-
lymphocytes capable of recognizing and destroying
virally infected cells. Moreover, acute EBV infection and
infectious mononucleosis can induce polyclonal B-
lymphocyte activation with generation of anti-neutrophil
antibodies and neutropenia.

58.  Initially, gingival inflammation permits herpes virus infected
inflammatory cells to enter the periodontium herpes virus
reactivation in the periodontium may then occur , which may
then aggravate the inflammatory response and accelerate the
existing disease.
 Thus, various immunosuppressive events may aggravate
periodontal disease, suggestive of accompanying herpes
virus activation.
 Active herpes virus infection decreases the resistance of the
periodontal tissues thereby permitting subgingival overgrowth
of pathogenic bacteria.
 The recognition that periodontitis is a multifactorial disease
involving herpes viruses , bacteria and host reaction may
explain why aggressive periodontitis is relatively uncommonin
most populations despite a high prevalence of individuals
harboring both herpes viruses and bacterial pathogens.

59. Herpesviral–bacterial
interactions in
periodontal
diseases
Jørgen Slots

60. Herpesviral–bacterial model
of
periodontitis

61. HEALTHY GINGIVA
BACTERIAL BIOFILM
GINGIVITIS
HERPESVIRUS
ACTIVATION
PERIODONTOPATHIC
PROPERTIES
1
1. Immunosupression
from infection or
cytotxic therapy
2. Inflammation
3. Psychosocial stress
or nutritional stress
4. Hormonal changes/
pregnancy
5. Physical or
chemical tissue
injury
6. Tobacco usage
7. Aging
8. others
Macrophages
with latent HSV
& CMV
B cells with
latent EBV
T cells with
latent HSV
&CMV

62. PERIODONTOPATHIC
PROPERTIES
Cytokines/chemokines/enzyme
s
1. interleukin- 1 beta
2. TNF – alpha
3. PG E2
4. Matrix metalloproteinases
Immunosuppresion and
upgrowth of exogenous – like
pathogenic bacteria
1. P.gingivalis
2. T.forsythia
3. A.actinomycetemcomitans
4. D. pnuemonsintes
1. Inflammation
2. Collagen degradation
3. Bone resorption
Sufficient time span
Destructive periodontal disease
Cytotoxicity/tissue
necrosis with severe
immunosuppresion
1. HIV infection
Nutritionally stressed
children/adolescentes

63. Periodontitis features Herpesviruses + Bacteria Bacteria alone
Dental plaque amount
and level
of dental care not
commensurate
with disease severity
Yes (herpesvirus active infection
in
the periodontium is not related
to dental plaque amount).
Yes (increased
occurrence of
specific
species of bacterial
pathogens in
certain plaques
Localized and bilateral
symmetry
of tissue breakdown.
Yes (herpesvirus infection
exhibits
tissue tropism, and tissue
around
similar teeth may show similar
propensity to attract
herpesviruses).
No
Intermittent exacerbation
of disease.
Yes (alterations between periods
of herpesvirus latency and
reactivation
, which may correspond to
disease stability and
Maybe (temporary
increase of
periodontopathic
bacteria due to
nonherpesviral
Likelihood of herpesviruses and bacteria explaining the disease
characteristics of periodontitis

64. Cemental hypoplasias
in teeth with
aggressive juvenile
periodontitis
Yes (active HCMV infection at the
time
of root development, which may
cause alterations in the tooth
surface).
No
Familial predisposition
to
disease
Yes (transmission of herpesviruses
within a family).
Yes (transmission of
pathogenic
bacteria within a
family).
Increased disease
prevalence
in lower socioeconomic
groups.
Yes (higher rates of herpesvirus
infection in individuals in lower
socioeconomic groups).
Maybe (individuals in
lower
socioeconomic groups
may harbor
increased levels of
periodontopathic
bacteria).
Increased alveolar
bone loss in
institutionalized
compared to
noninstitutionalized
mentally
retarded individuals.
Yes (high rate of herpesvirus
transmission in institutionalized
individuals).
Unlikely (poor oral
hygiene in
institutionalized
individuals

65. Occlusal trauma as a risk
indicator of disease.
Yes (trauma may induce
herpesvirus reactivation).
Unlikely (slightly
increased occurrence
of periodontopathic
bacteria with
increased mobility).
Immunodeficiency
predisposes
to increased incidence ⁄
prevalence
of disease.
Yes (immunosuppression is
an
important event in
herpesvirus
reactivation)
Unlikely (some pathogenic
bacteria
possess
immunosuppressive
properties).
Old age as a risk indicator
of disease.
Yes (reduced immune
capacity
and increased herpesvirus
occurrence with increasing
age).
Maybe (increased
acquisition of
pathogenic bacteria over
time).
HIV-infection as a risk
indicator
of disease.
Yes (most HIV-infected
patients
harbor several periodontal
herpesviruses that have the
potential to reactivate
frequently
due to the
immunosuppression).
Unlikely (HIV and non-HIV
patients
harbor similar
periodontopathic
Microbiota

66. Psychosocial stress as
a risk indicator of
disease.
Yes (stress can
induce herpesvirus
reactivation
Maybe (host-derived nutrients
in
gingival crevice fluid of
stressed
individuals may stimulate[or
inhibit] the growth of selected
bacterial species
Hormonal influences on
periodontal disease.
Yes (hormones and
progesterone
may increase the
susceptibility
to herpesvirus
infections).
Maybe (sex hormones may
serve
as growth factors for some
periodontopathic bacteria).
Cigarette smoking as a
risk
indicator of disease.
.
Yes (tobacco
products can interact
with
and possibly
reactivate periodontal
herpesviruses or act
synergistically
with HCMV to
enhance the
sensitivity
of peripheral blood
Unlikely (some anaerobic
periodontal
bacteria may occur at increased
levels in smokers)

67. Disease progression in
the
presence of elevated
antibacterial antibodies.
Yes (herpesvirus
active infection is
not controlled by
antibacterial
antibodies).
Possibly (if antibodies
are directed
against noncritical
antigens, or
against nonaccessible
bacteria in
biofilms, or are part of
immunopathologic
mechanisms
of tissue destruction).
Predominance of T-
lymphocytes
in relatively stable and
B-lymphocytes in
progressive
periodontitis lesions
Yes (HCMV and HSV
reside in
T-lymphocytes and
EBV resides
in B-lymphocytes
Unlikely, if not an
immunopathologic
mechanism of tissue
breakdown is
postulated
Defective neutrophil
functions associated with
aggressive Disease
Yes (herpesviruses
may infect and
perturb neutrophils).
Unlikely (some bacterial
species
may perturb neutrophils

68. Occurrence of CD8+
and
Th1-type
lymphocytes in
periodontitis.
Yes (herpesvirus
active infection
leads to increased
level of cytotoxic
CD8+ cells)
Unlikely (a few
bacterial species
may stimulate T-
suppressor
cells).
Possible relationship
between
periodontal disease
and major
medical disorders
(coronary heart
disease,
cerebrovascular
disease,
low birth weight
infants).
Yes (herpesviruses
may induce both
periodontitis and
medical disorders;
if so, periodontitis and
medical disorders
may not exhibit a
direct causal
relationship).
Still to be resolved.

69. Salient features of periodontal
disease pathogenesis and
herpes viruses
 The probable pathogenesis is based on:
 1) Presence of nucleic acid sequences of EBV-1 and HCMV
and other herpesviruses in juvenile and adult periodontitis
lesions;
 2) The association between herpesviruses and acute
necrotizing gingivitis
 3) The demonstration of mRNA gene HCMV expression in
adult and localized juvenile periodontitis lesions and the
apparent association with progressive disease.
 4) The demonstration of increased frequency of
periodontopathic bacteria in heresvirally positive periodontitis
lesions
 5) The detection of nucleic acid sequences of herpesviruses
in inflammatory periodontal cells

70.  6) The probable prominent effect of herpesvirus infection on
periodontal defense cells.
 7) The ability of herpesviruses to augment the expression of
tissue-damaging cytokines in periodontal inflammatory cells.
 The suggestion is that gingival infection with certain
herpesviruses decrease the resistance of the periodontal
tissue, thereby permitting subgingival overgrowth of
periodontal pathogenic bacteria.
 Herpesvirus reactivation in periodontal tissue resulting in
transient immunosuppression might in part explain the
episodic progressive nature of human periodontitis.
 Tissue tropism in herpesvirus infection might help explain the
localized pattern of destruction in many cases of periodontitis.
 Absence of periodontal herpesvirus infection or reactivation
could allow for some individuals carrying periodontopathic
bacteria in their subgingival microbiota while maintaining
periodontal health

71. Antiviral host response
 Both cellular and humoral immunity responses are recruited
in viral infections.
 Enveloped viruses typically initiate cell-mediated
inflammatory responses and delayed type hypersensitivity,
which affect viral replication by killing mammalian cells that
express viral proteins.
 Naked viruses are controlled mainly by antibody, and
vaccines are generally effective.
 The role of humoral immunity is to produce antibodies against
proteinaceous surface structures and thereby cause
inactivation or clearance of the virus. Conversely,viruses have
developed important means of escaping from immune
detection, and have redirected or modified a normally
protective host response to their advantage.

72. Diagnostic Aids
 Traditional methods:
 Cell culture to detect characteristic cytopathic
effects, morphologic determination of
intracytoplasmic and intranuclear inclusion
bodies,
 Immunohistochemical techniques,
immunoassays to identify viral antigens in
clinical specimens,
 or the measurement of total or class-specific
antibodies against specific viral antigens. In
some viral infections, IgM antibodies are
useful for determining primary infection, and
IgG antibodies for assessing the susceptibility
to primary infection and viral reactivation.

73.  Recent techniques
 Viral nucleic acid can be measured
directly by hybridization, or be
detected after amplification by nucleic
acid amplification methods.
 Polymerase chain reaction (PCR)
 Microarray-based detection assay

74. Therapeutic implications
 Conventional periodontal therapy can reduce the
periodontal load of herpesviruses.
 Mechanical debridement has suppressed subgingival
Epstein– Barr virus to undetectable levels in 12 of 21
patients, and has decreased subgingival Epstein–Barr
virus genome-copies by sixfold and subgingival
cytomegalovirus genome-copies by 38-fold. (Saygun I,
Kubar A, O¨ zdemir A, Slots J., J Periodontal Res 2005)
 After repeated debridement, 24 patients with
periodontitis yielded no cytomegalovirus, but were
found to have Epstein–Barr virus and herpesvirus-7,
suggesting that cytomegalovirus is particularly
susceptible to the effects of periodontal therapy.
(Rotola A, Cassai E, Farina R, Caselli E, Gentili V, Lazzarotto T,
Trombelli L., J Clin Periodontol 2008)

75.  Anti-herpesvirus chemotherapy can also decrease the
salivary viral load.
 A short course of valacyclovir, 2 g twice on the day of
treatment and 1 g twice the following day, resulted in a
significant decrease in the salivary occurrence of
Epstein–Barr virus compared with controls . (Miller CS,
Avdiushko SA, Kryscio RJ, Danaher RJ, Jacob RJ. , J Clin Microbiol
2005)
 Valacyclovir, 500 mg orally twice daily for 1 month,
given to elite male distance runners, reduced the
salivary load of Epstein–Barr virus by 82% compared
with placebo. Valacyclovir therapy, 3 g 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 . (Cox AJ,
Gleeson M, Pyne DB, Saunders PU, Clancy RL,Fricker PA., Med Sci
Sports Exerc 2004)
 Chemotherapeutics are effective against viruses in the
lytic phase, but not against viruses in the latent phase,
limiting their potential use to disease-active infections.

76.  Future management of periodontal
diseases may benefit from anti-
herpesviral immunotherapeutics:
 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.

77. Conclusion
 Despite circumstantial evidence of role
of herpesvirus in destructive
periodontal disease, a cause and
effect relationship remains to be
established.
 Further investigations are required to
prove the possible involvement of
herpesviruses.

78. BIBLIOGRAPHY
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children , Matti Sa¨ Llberg
 J. Int Oral Health 2010, August 2010, Volume 2 (Issue 2) Page 59
 Herpesviruses in Human Periodontal disease. Reality or Myth…?
Pushpa S P MDS* Soumya B G MDS
 Periodontology 2000, Vol. 38, 2005, 33–62, Herpesviruses in
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 Periodontology 2000, Vol. 49, 2009, 60–86 Oral viral infections of
adults Jørgen Slots
 Periodontology 2000, Vol. 53, 2010, 89–110 Human viruses in
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