oral infection and systemic diseases, Influence of viral infections on epithelial barrier function

1. Oral Infection and
systemic diseases
By
Romissaa Aly
Assistant lecturer of Oral Medicine, Periodontology,
Diagnosis and Dental Radiology (Al-Azhar University)

2. The epithelium is a unique barrier that separates the body from
its environment.
The basic structure of the oral mucosa is similar to that of
human skin. It consists of two layers: an epithelium with a
basement membrane; and an underlying connective tissue (lamina
propria) that includes the supra-alveolar fiber apparatus, blood,
lymphatic vessels and nerves .
Essential functions of oral mucosal barriers are resistance against
pathogens, exogenous substances and mechanical stress .

3. The epithelium of the gingiva and papillae is a stratified squamous
keratinized epithelium, whereas the oral sulcular epithelium is
stratified squamous and nonkeratinized.
The junctional epithelium is squamous and nonkeratinized and
although it does not exhibit true phenotypic stratification, the
outermost cells tend to be
elongated and to lie with their long axis parallel to the tooth surface .

4. The gingival connective tissue consists of a dense network of collagen
fibers that are able to provide firmness to the gingiva and to attach the
gingiva to the underlying cementum and alveolar bone.
The connective tissue of the gingiva is also rich in lymphatic and blood
vessels, nerves and many cells specific to immune–inflammatory and
vascular systems.

5. A characteristic feature of the epithelium is its exceptionally high rate of
cellular
turnover, which is much higher than in skin.
 This high turnover rate provides an effective barrier to bacterial
penetration.
 The gingival epithelial turnover time was found to be 5–11 days in
primates and 3–5 days in mice.
The protective function of the gingival epithelium is also enhanced by
saliva secretion, which physically lubricates the epithelial surfaces and

6. Cytokeratins are considered to be molecular markers for
different types of epithelialdifferentiation.
Gosselin et al. demonstrated that reconstituted gingival
epithelium in vitro expressed some cytokeratins that are
specific for embryonic, simple and tumor epithelia, whereas
gingival epithelium reconstituted on a connective tissue
equivalent expressed all cytokeratins present in the normal
gingival tissue.

7. These results suggest that the culture of gingival
keratinocytes on connective tissue equivalents enables them
to mimic the physiological stages of differentiation .

8. The basal cells form the proliferating layer of the epithelium
and attach to the lamina densa of the lamina basalis through
hemidesmosomes.
The spinous cell layersare specialized for cell–cell contacts by
many desmosomes.
Cell–cell contacts via gap junctions are also abundant.

11. Apoptosis is a suicidal program leading to the elimination of
individual cells, whereas programmed cell death during epidermal
development results in cornification of the keratinocytes that
establish a tight barrier of dead cells protecting the
organism from the environment.

12. Furthermore, the molecular signal-transduction pathways and
regulatory mechanisms of apoptosis and cornification of
keratinocytes are clearly different .

13. Epithelial tissues provide a barrier between the body and the
environment, and keratinocytes form the first line of defence
against bacterial challenge .
Gingival keratinocytes are connected to each other by a variety
of specialized transmembrane proteins .

14. Structural components of tight junctions consist of a large number
of different proteins, such as occludin , occludin
1B , zonula occludens protein-1 , zonula occludens protein-2 and
zonula occludens protein-3 , as well as members of the protein
family of claudins .

15. Claudins have barrier properties and directly regulate the gate
function as paracellular tight-junction channels.
These structures have biophysical properties that are similar to
those of traditional ion channels.
Another property is that they also recruit occludin to tight
junctions .

18. Adherens junctions are protein complexes that occur at cell–cell
junctions in epithelial and endothelial tissues and are localized
usually more basal than are tight junctions.
An adherens junction is defined as a cell junction whose
cytoplasmic face is linked to the actin cytoskeleton

19. Adherens junctions may appear as bands encircling the cell
(zonula adherens) or as spots of attachment to the
extracellular matrix (adhesion plaques).
Adherens junctions are cell-to-cell adhesion sites in which
classic cadherins function as cell adhesion molecules and
where the actin-based cytoskeleton and several cytoplasmic
components are assembled .

20. Adherens junctions are established via calcium-
dependent hemophilic binding of the extracellular
cadherin domains.

22. Gap junctions are aggregates of intercellular channels between
adjacent cells that mediate reciprocal exchange of metabolites and
ions of <1 kDa in molecular mass, including second messengers,
such as cyclic adenosine monophosphate and Ca2+.
These intercellular channels are formed by head-to-head
docking of hexameric assemblies (connexons) of tetraspan
integral membrane proteins, the connexins
(Fig. 7) .

23. Connexins and innexins are universally used to promote
intercellular interactions between cells in solid tissues and
circulating elements of the blood, and show multiple levels of
regulation.
Genetic studies have shown that gap junctions are involved in
a wide variety of functions in homeostasis, regulation, regeneration
and development.

24. The dysfunction of gap junctions is believed to be associated with
cancer development.
The expression of connexin 43, one of the major connexins in oral
epithelia, was investigated in rat tongue carcinoma.
The results indicated that down-regulation of connexin 43 might be
an early event during oral carcinogenesis, which could be a biomarker
for early changes in oral malignant transformation .

26.  The set-up of the in vitro test system for transepithelial
electrical resistance measurements is shown.
A close correlation between the number of junctional strands and
junctional tightness, as judged by transmural resistance values, was
demonstrated.
The correlation between tight junctions and the transepithelial
electrical resistance was also shown in primary human gingival
keratinocytes .

28. Among all microorganisms in the oral cavity, some periodontal
pathogens (Aggregatibacter actinomycetemcomitans,
Porphyromonas gingivalis, Tannerella forsythia and Treponema
denticola) are able to induce inflammatory responses that lead to
attachment loss and periodontal destruction.
Porphyromonas gingivalis is an anaerobic gram-negative
coccoid rod that exhibits a variety of virulence factors.

29. This microorganism is considered as one of the primary
microbiological factors involved in the pathogenesis
of periodontitis and has recently been described as a ‘keystone
pathogen’.
Some strains of P. gingivalis produce a number of proteolytic
enzymes, such as gingipains, amino peptidases, invasins,
cytotoxic substances, collagenases , lipopolysaccharide
, outer membrane proteins, fimbriae and capsule proteins .

30. Porphyromonas gingivalis ATCC 33277, one of the best-
characterized strains, expresses fimbriae , and is able to produce
gingipains and to invade oral cells ; however, invasion of P. gingivalis
ATCC 33277 can be inhibited by protease inhibitors.
Fimbriated P. gingivalis strains are more effective in entering human
dendritic cells than are fimbriae-deficient strains .

31. Cytokines and chemokines of the
epithelial barrier in periodontal
infection

32. Histological studies revealed that oral keratinocytes express a variety
of proinflammatory cytokines and chemokines, including interleukin-
1alpha, interleukin-1beta, interleukin-6, interleukin-8 and tumor
necrosis factor-alpha.

33. Interleukin-1, interleukin-8, interleukin-6 and tumor necrosis
factor-alpha are essential in the developmentm of inflammatory
reactions and are involved in both the local and the systemic immune
response to bacterial antigens.
Interleukin-8 is crucial in the local defense against micro-organisms
because of its function as a chemokine directing neutrophil
migration .

34. In a mouse model it was shown that overexpression of
interleukin 1alpha caused a syndrome that possessed the
cardinal features of periodontal disease, including epithelial
proliferation and apical migration, loss of attachment and
destruction of cementum and alveolar bone .

35. Interleukin-6 can act as a proinflammatory and anti inflammatory
cytokine.
It is secreted by T-cells and macrophages to stimulate immune
responses during infection and tissue damage leading to
inflammation.
 Increased levels of interleukin- 6 were shown in the crevicular fluid
of inflamed periodontal pockets compared with healthy
sites

36. Interleukin-8 is also known as neutrophil chemotactic
factor because of its functions.
It induces chemotaxis in neutrophils and other granulocytes,
causing them to migrate toward the site of infection (14, 15).
 High levels of interleukin-8 were detected in crevicular
fluid and gingival tissue from patients with periodontitis
.

37. The significance of tumor necrosis factor-alpha in the
development of periodontitis has been linked mainly to its ability
to induce connective tissue destruction and bone resorption

38. Role of epithelial-derived matrix
metalloproteinases in periodontal
infection

39. Matrix metalloproteinases are zinc-dependent endopeptidases
that are able to degrade all types of extracellular matrix proteins and
can process a number of bioactive molecules.
They are known to be involved in many important processes, such as
cell proliferation, differentiation, migration and death, as well as
in cell–cell interactions.

40. Matrix metalloproteinases 2 and 9 are both type IV collagenases
that are capable of degrading denatured interstitial collagens, gelatins,
laminin and fibronectin , elastin and basement membrane-
zone-associated collagens type IV and type VII .
In the oral cavity, the main source of type IV collagenases has been
suggested to be polymorphonuclear granulocytes that migrate into
the oral cavity through the gingival sulcus.

41. The alternative name for matrix metalloproteinase-3 is
stromelysin-1, an enzyme that degrades collagen types II, III, IV, IX
and X, proteoglycans, fibronectin, laminin and elastin. In
addition, matrix metalloproteinase-3 can also activate
other matrix metalloproteinases, such as matrix metalloproteinases
1, 7 and 9 .

42. Matrix metalloproteinase-8, also known as neutrophil collagenase or
as collagenase-2, is a collagen-cleaving enzyme and the major
collagenase species detected in inflamed human periodontium.
.

43. Matrix metalloproteinase-13 is also termed collagenase-
3 and plays a role in the degradation of collagenous
matrix.
In addition to fibrillar type I, XI and III collagens, it degrades
type IV, IX, X and XIV collagens, gelatin, tenascin-C, fibronectin
and proteoglycan core proteins

44.  In cultured porcine periodontal ligament cells, expression of
matrix metalloproteinase-13 was enhanced by tumor
necrosis factor-alpha, transforming growth factorbeta1
and by keratinocyte growth factor in the presence of heparin.
Expression of matrix metalloproteinase- 13 was induced in non
differentiated epithelial cells during chronic inflammation as a result of
exposure to cytokines and collagen .

45. Matrix metalloproteinase-24 (also known as membrane
type1-matrix metalloproteinase) is a membrane- anchored type-1
matrix metalloproteinase.
Although not classified as a member of the collagenases group, it
has been demonstrated that this matrix metalloproteinase plays a
physiologically relevant role in type-I collagen remodeling (87).

46. In summary, the expression of different matrix
metalloproteinases in normal and diseased human gingiva
might contribute to periodontal physiological
and pathological processes.

52. Influence of viral infections
on
epithelial barrier function

53. These data suggest that HIV-associated tight junction
disruption of the mucosal epithelia may potentiate human
papillomavirus infection and subsequent development of human
papillomavirus-associated neoplasia.

54. Human papilloma viruses infect mucosal and cutaneous epithelia
and induce lesions that can persist and progress to cancer; this is
particularly so for human papillomaviruses 16 and 18.
The human papillomavirus- 16 genome encodes three
transforming proteins: E5, E6 and E7 .

55. Progression of most solid tumors is characterized by an
increase in secretion and activation of matrix
metalloproteinases produced by either the tumor cells or
tumor-associated fibroblasts.

56. Using three-dimensional organotypic raft cultures, Barbaresi et al.
(17) showed that HaCaT human keratinocytes, expressing human
papillomavirus- 16 E5, formed a perturbed epithelium
with defective differentiation, invasion into the collagen matrix,
progression through the cell cycle and production of matrix
metalloproteases, especially of matrix metalloprotease-9.

57. Epstein–Barr virus is a human herpesvirus that infects both
lymphoid and epithelial cells and contributes to the pathogenesis of
several lymphomas and carcinomas.
Using a lytic transactivator of Epstein– Barr virus induction of matrix
metalloprotease-3 expression, migration and invasion of Epstein–Barr
virus-infected cells has been demonstrated .

58. Chronic or dysregulated inflammation has long been appreciated
as contributing to tumor development, in part through
modulation of the tumor microenvironment .
Both P. gingivalis and F. nucleatum establish chronic infections that
involve intracellular persistence within epithelial cells, can spread
systemically and cause extra-oral infections, and have well-
characterized immune disruptive properties.

59. F. nucleatum is strongly proinflammatory, and McCoy et al. [7]
demonstrated a positive correlation between mRNA levels for several
local cytokines and Fusobacterium species in CRC cases.
 Furthermore, in the ApcMin/+ mouse model of intestinal
tumorigenesis, F. nucleatum recruits tumor-infiltrating
immune cells, thus generating a proinflammatory microenvironment
that is conducive for CRC progression.

60. Remarkably, P. gingivalis possesses multiple mechanisms for
inhibition of apoptosis in epithelial cells.
Expression of microRNAs (miRs) is modulated, and up-
regulation of miR-203 leads to inhibition of the negative
regulator SOCS3 and subsequent suppression of apoptosis.

61.  F. nucleatum also activates p38, leading to the secretion of MMP-9
and MMP-13 (collagenase 3).
Similar to MMP-9, MMP-13 plays an important role in tumor
invasion and metastasis.
Recently, a more direct relationship between F. nucleatum and
CRC was demonstrated whereby the fusobacterial adhesin FadA
binds to E-cadherin on colon cancer cells and activates b-catenin
signaling .

64. Oral infections and systemic diseases

65. Cardiovascular disease and periodontitis
 It is well known that bacteremia occurs after extraction, scaling, and
probing .
Also, less invasive procedures such as removal of sutures and
conservatory dentistry procedures such as drilling and placement of
rubber dam, matrix band, and wedges may cause bacteremia .
Bacteremia after mastication and oral hygiene procedures
is not uncommon.

66. Compared with bacteremia caused by treatment in the dental
office, multiple daily bacteremias implies a large microbial burden
on the organism due to a cumulative effect and may be the most
serious factor in the development of chronic disease.
Periodontal inflammation facilitates the entrance of bacteria into
the bloodstream .

67. The significance of bacteremia with oral bacteria may depend
on the type of bacteria transferred to the bloodstream.
Porphyromonas gingivalis, considered an important pathogen
in the development of periodontitis, may induce thrombus
formation by aggregating platelets [36].
Because traces of Porphyromonas gingivalis have been revealed
in coronary and carotid atheromas , such a pathway may be
important.

68. Platelets also may interact with supragingival plaque bacteria
because they appear to selectively bind strains of Streptococcus
sanguis, which result in thrombus formation .

69. An indirect pathogenic role of periodontal bacteria may be
due to the influx of inflammatory cells into large blood
vessels in association with bacteremia and
lipopolysaccharide produced by gram-negative bacteria.

70. The resulting production of cytokines such as interleukin (IL)-1b
and tumor necrosis factor (TNF), prostaglandins, and growth factors
including platelet-derived growth factor, fibroblast growth factor,
and granulocyte macrophage colony-stimulating factor may
contribute to thickening of the arterial wall because several of these
substances are atherogenic .

71. Another pathway may be that the inflammatory response
associated with periodontitis elevates the levels of acute-phase
proteins including fibrinogen and C-reactive protein in the general
circulation .
Because fibrinogen and C-reactive protein are risk factors for CVD ,
this also may explain a link between CVD and periodontitis.

72. Possible biological mechanisms linking periodontal and
cardiovascular disease include molecular mimicry between the
bacterial heatshock protein GroEL and human heat-shock protein 60
(hHSP60).
This hypothesis, first suggested by Wick et al., involves
crossreactivity between the immune response mounted against a
bacterial infection and hHSP60 expressed on stressed or damaged
endothelial cells.

73. Yamazaki et al. [41] have shown that T-cells reactive with both
GroEL and hHSP60 have identical nucleotide sequences in their T-
cell receptor b-chain genes, and that such T-cells exist both in the
atherosclerotic plaques themselves and in the periodontal tissues.

74. Metastatic inflammation.
Soluble antigen may enter
the
bloodstream, react with
circulating specific antibody,
and form
a macromolecular complex.
These immunocomplexes
may give
rise to a variety of acute and
chronic inflammatory
reactions at
the sites of deposition.

77. Periodontal pathogens may summon polymorph nuclear leukocytes
and monocytes.
This process may generate oxidative stress as well as periodontal
tissue destruction.
 Reactive oxygen intermediates produced by this stress may oxidize
low-density lipoprotein cholesterol, which is a risk factor for CVD.

78. Concurrently, the by-products of these leukocytes may stimulate
the liver to express CRP, IL-6, fibrinogen, and other
proinflammatory mediators.
These molecules in turn initiate the inflammatory process leading
to atheroma formation in the endothelium.

85. Diabetes mellitus and periodontitis
Patients with DM of long duration appear to be
characterized by more frequent and more advanced loss of
attachment, and the periodontal health may deteriorate more rapidly
in poorly controlled diabetics than in control patients without DM .

86. Impaired function of neutrophils, including reduced chemotaxis
, adherence , and phagocytosis, may be the most
significant factor leading to increased susceptibility to
periodontal disease.

87. Pneumonia and oral bacteria
Respiratory pathogens may also be harbored in subgingival
bacterial samples.
Isolates from deep periodontal pockets have demonstrated
the presence of Enterobacteriaceae , and other researchers
have isolated the same organisms in 8% and Staphylococcus
aureus from 46% of periodontitis patients .

88. In addition to these findings, it has been reported
that the offending organisms in suppurating respiratory anaerobic
infections with considerable mortality most often originate from the
subgingival environment .

92. Rheumatoid arthritis and
periodontitis
Periodontitis and rheumatoid arthritis share several characteristics.
They are both clinically characterized by local destruction of hard and
soft tissue as a consequence of an inflammatory response.
During the inflammatory response, local cells are stimulated to
release cytokines and matrix metalloproteinases, factors that are
essential in the pathogenesis of both diseases.

93. An altered function of the inflammatory response and the
metabolism of soft and hard tissues (caused, for example, by
genetic polymorphisms that possibly alter the cytokine and
matrix metalloproteinase expression) may turn out to be
identical pathogenic factors.

97. Preterm birth and low birth
weight
Because prostaglandins stimulate the myometrium in the
uterus, the amount of the prostaglandins PGE2 and PGE2a in
chorion is decisive for the onset of labor.
The syntheses of prostaglandins increase under the influence of
the cytokines IL-1, IL-6, and TNF.

98. Periodontitis causes bacteremia, with gram-negative bacteria
releasing lipopolysaccharides, and this bacterial product initiates the
production of cytokines by inflammatory cells.
These cytokines may stimulate the production of prostaglandins in
chorion, resulting in labor .

100. oral infection be a risk factor
for Alzheimer's
disease

101. Alzheimer’s disease (AD) is a scourge of longevity that will
drain enormous resources from public health budgets in the
future.
Currently, there is no diagnostic biomarker and/or treatment for
this most common form of dementia in humans. AD can be of
early familial-onset or sporadic with a late-onset.

102. Apart from the two main hallmarks, amyloid-beta and
neurofibrillary tangles, inflammation is a characteristic feature of
AD neuropathology.
Inflammation may be caused by a local central nervous system
insult and/or by peripheral infections.

103. Numerous microorganisms are suspected in AD brains ranging from
bacteria (mainly oral and non-oral Treponema species), viruses (herpes
simplex type I), and yeasts (Candida species).
A causal relationship between periodontal pathogens and non-oral
Treponema species of bacteria has been proposed via the amyloid-
beta and inflammatory links.

104. Periodontitis constitutes a peripheral oral infection that can
provide the brain with intact bacteria and virulence factors and
inflammatory mediators due to daily, transient bacteremias.
If and when genetic risk factors meet environmental risk factors in
the brain, disease is expressed, in which neurocognition may be
impacted, leading to the development of dementia.

106. The most likely pathway for dissemination of oral microorganisms to
the brain is through the blood stream.
Dental treatment as well as brushing, flossing, chewing,
and use of tooth picks in a patient with periodontitis will
release a bacteremia.
This can occur several times during the day and has been estimated
to last for up to 3 hours for oral bacteria.

107. The bacteremia is usually contained by immune cells of the
body. However, in people with reduced immune defense, e.g.
older individuals, bacteria may localize to crevices of the oral
cavity and vascular channels.

108. An intact BBB prevents microorganisms in the blood from accessing
the brain. However, aging favors overgrowth of oral microorganisms,
particularly anaerobic bacteria and facultative yeasts that established
earlier in life and provoked pro-inflammatory responses that
weakened the BBB .

109. Notably, magnetic resonance imaging (MRI) confirmed loss of
BBB integrity in a mouse model of disseminated candidosis .
 Loss of integrity allows microorganisms to spread through the
blood stream and quietly contribute in the pathogenesis
of AD.

110. Nanoparticles and the control of oral infections

111. The potential of antimicrobial nanoparticles to control oral
infections is reviewed. Such particles can be classified as
having a size no greater than 100 nm and are produced using
traditional or more novel techniques..

112. Exploitation of the toxic properties of nanoparticles to bacteria,
fungi and viruses, in particular metals and metal oxides, as well as
their incorporation into polymeric materials have increased
markedly over the past decade.
The potential of nanoparticles to control the formation of
biofilms within the oral cavity, as a function of their biocidal, anti-
adhesive and delivery capabilities, is now receiving close attention

113. For example, the antimicrobial effectiveness of metallic
nanoparticles has been suggested to be due both to their size
and high surface-to-volume ratio.
In theory, these characteristics should allow them to interact
closely with microbial membranes and thus elicit an
antimicrobial effect that is not solely due to the release of
metal ions.

116. Photodynamic therapy
and the use of
nanoparticles to control
oral biofilms

117. Biofilms Photodynamic therapy is very well suited for the
control of bacteria in oral plaque biofilms where there is
relatively easy access for application of the photosensitising
agent and light sources toareas requiring treatment .

118. Killing of micro-organisms with light depends upon cytotoxic
singlet oxygen and free radical generation by excitation of a
photoactivatable agent or sensitiser.
The result of excitation is that the sensitiser moves from an
electronic ground state to a triplet state, which then interacts with
microbial components to generate cytotoxic species.

119. One of the advantages of light-activated killing is that resistance to
the action of singlet oxygen is unlikely to become widespread in
comparison with that experienced with more traditional chemical
antimicrobial agents.
The most commonly tested sensitisers on bacteria havebeen tricyclic
dyes (e.g. methylene blue, erythrosine), tetrapyrroles(e.g. porphyrins)
and furocoumarins (e.g. psoralen). Use of nanopar-ticles within this
area is now receiving attention.

120. The safe use of nanotechnology and the design of
nanomaterials for biological applications involve a thorough
understanding of the interface between these materials and
biological systems.
The interface comprises three interacting components: (i) the
surface of the nanoparticle; (ii) the solid–liquid interface and the
effects of the surrounding medium; and (iii) the contact zone with
biological substrates.

121. The nanoparticle characteristics of most importance with regard
to interaction with biological systems, whether mammalian or
microbial, are chemical composition, surface function, shape and
number of sides, porosity and surface crystallinity, size heterogene-
ity, roughness, and hydrophobicity or hydrophilicity.

122. Anti-adherent and antifungal effects were shown using buccal
epithelial cells treated with non-drug-loaded poly(ethylcyanoacrylate)
nanoparticles.
Nanoparticles were prepared using emulsion polymerisation and
were stabilized with cationic, anionic or non-ionic surfactants.
Cationic surfactants, e.g. cetrimide, whichare known antimicrobial
agents, were the most effective inreducing C. albicans blastospore
adhesion and demonstrated agrowth-inhibitory and biocidal effect
against the yeast.

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