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Microbial Pathogenesis
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Keywords: Periodontitis is an infectious inflammatory disease resulting from infection of biofilm forming bacteria. Several
Oral spirochetes bacterial factors regulate inflammatory response and cause to tissue damage and loss of connection between
Periodontitis gingival and tooth. Since bacterial virulence factors and also host immune responses have role, understanding of
Treponema denticola periodontal disease is complex, in overall we can say that in this disease epithelium is deleted by bacteria. Oral
Oral infection
spirochetes are related to periodontitis, among them, Treponema denticola, have been associated with periodontal
diseases such as early-onset periodontitis, necrotizing ulcerative gingivitis, and acute pericoronitis. This review
will analyse mechanisms of pathogenesis of spirochetes in periodontitis. Microorganisms cause destruction of
gingival tissue by two mechanisms. In one, damage results from the direct action of bacterial enzymes and
cytotoxic products of bacterial metabolism. In the other, only bacterial components have role, and tissue de-
struction is the inevitable side effect of a subverted and exaggerated host inflammatory response to plaque
antigens.
Corresponding author. Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
∗
E-mail addresses: yousefileila94@gmail.com (L. Yousefi), hamedebr7@gmail.com (H.E. Leylabadlo), t.pourlak@gmail.com (T. Pourlak),
eslamihosein56@yahoo.com (H. Eslami), sepehrtaghizadeh10@gmail.com (S. Taghizadeh), khuda1949@mail.ru (K. Ganbarov),
yousefime@tbzmed.ac.ir (M. Yousefi), tanomanda@yahoo.com (A. Tanomand), yousefib@tbzmed.ac.ir (B. Yousefi), Kafilhs@tbzmed.ac.ir,
kafilhs@tbzmed.ac.ir (H.S. Kafil).
https://doi.org/10.1016/j.micpath.2020.104193
Received 21 February 2020; Accepted 7 April 2020
Available online 15 April 2020
0882-4010/ © 2020 Elsevier Ltd. All rights reserved.
L. Yousefi, et al. Microbial Pathogenesis 144 (2020) 104193
Table 2
Summary of virulence factors of T. denticola.
Virulence factors Activity References
Motility and Chemotaxis dmcA gene encodes homologue methyl-accepting chemotaxis proteins [106,107]
T. denticola preplasmic flagella in addition to motility has influence on helical morphology of bacteria
Adhesins A53 kDa weight protein Binding to fibronectin [5]
OppA A 72 KDa protein that binds to fibronectin [5,108]
Flagellin Binding to fibronectin [5]
Lectin-like adhesion Has affinity to mannose and galactose on fibroblast surface [5]
Factor present in host serum Binding the bacterium to fibroblasts [5]
Msp Mediates the adhesion to extracellular matrix (ECM) components [56]
Transporting Metal Haemin binding protein Iron acqusition [85,109]
Lactoferrin binding protein Iron acqusition [85,109]
Hemolysin Lyses erythrocytes for causing heme compounds [85]
Enzyme Dentilisin Degrades fibronectin, laminin and type IV collagen and serum proteins including fibrinogen, transferrin, [32]
IgA, IgG and α 1-antitrypsin
PLC Hydrolyzing membrane phospholipids [110,111]
Serine protease Has chymotrypsin-like activity [24]
Phospholipase C Hydrolyzing phosphatidylcholine [110]
Trypsin-like Hydrolysis of benzoyl-DL- arginine-2-naphthylamide (BANA) [101]
Chymotrypsinlike Degrades immunoglobulin A, immunoglobulin G, α1-antitrypsin, BSA, transferrin, gelatin and fibrinogen [79]
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L. Yousefi, et al. Microbial Pathogenesis 144 (2020) 104193
showing that OMVs presumably penetrate blood vessels [31]. This specific and requires receptors on the surface of the host cells [43].
might be in relation with the recent subject that periodontitis may in- Other non-specific factors like charge and hydrophobic attractions have
fluences on systemic diseases [32,33]. We summarize some related also important role in adherence of bacteria to host cells. Binding of
mechanism action and metabolites used by spirochetes that lead to bacteria to extracellular matrix molecules, like collagen, fibronectin,
elucidation of spirochete virulence properties including motility, che- and laminin, also are of importance to infective process [44]. Some
motaxis, adherence to host cells, colonization, Lipopolysaccharides, bacteria use specialized structures like fimbriae for binding to host
toxins, enzymes and transporting metals. The mechanism action of as- surface or other bacteria, but spirochetes attachment has not been un-
sociated with periodontitis as shown in Figure- 1. derstood [45]. Although, attachment of T. denticola to specific host cells
is important for causing disease, but we have little information about its
2.1.1. Motility and chemotaxis mechanism [46]. Studies have shown that attachment to cultured cells
Motility and chemotaxis is a kind of virulence factor and their role is a characteristic that is seen just in pathogenic organisms, since ad-
in spirochetes is important. When T. denticola is present in a tissue, herence of the Reiter treponeme and T. denticola to fibroblast cell lines
intracellular contact destroys [34]. Oral spirochetes by mechanisms like and testicular cells was not seen [47]. T. denticola attach to fibroblasts
other spirochetes invade to tissue by immigrating between intracellular and epithelial cells, and mucopolysaccharides such as hyaluronidase is
[35]. Motility systems of oral spirochetes is suited for high viscosity receptor on epithelial cells. T. denticola and T. vincentii have enzymatic
environments, and motility of T. denticola is depended on viscosity activity that is essential in invading of the organism to gingival epi-
[36,37]. There are some genes that are involved in motility and che- thelium, also Treponemes could attach to matrix proteins like fi-
motaxis of T. denticola, for example, the fliG, fliF, fliH, flgB, flgC and fliE bronectin in pellicle [48]. T. denticola binds to hydroxyapatite beads
genes although these genes present also in other bacteria [38,39], also, coated with lysosome or fluids. T. denticola also binds to laminin. A
dmcA gene encodes homologue methyl-accepting chemotaxis proteins four-amino-acids site including arg-gly-asp-ser on fibronectin is binding
and is located in upstream of prtB gene which encodes chymotrypsin region of spirochetes. Binding site for laminin on T.denticola is the same
like activity in T. denticola [40,41]. T. denticola preplasmic flagella in for fibronectin and this leads to steric hindrance [49].
addition to motility has influence on helical morphology of bacteria
[42]. Periodontitis can be predicted by the flagella [3]. Table- 1 shows 2.1.3. Adhesin proteins
used methods for detecting some of the motility genes and some of In addition to enzymatic activities, toxic effects of peptidoglycan are
these genes that are involved in the periodontitis. important in binding of the organism to eukaryotic cells [50]. T. den-
ticola has a 56–58 kDa weight protein on its surface and at least four
2.1.2. Adherence to host cells various proteins have been involved as adhesins of T. denticola [39].
It has been established that adherence of bacteria to host cells is Three proteins in T. denticola (53 and 72 kDa and flagellin) have been
initial step in development of infection. In most of bacteria this is identified for binding to fibronectin [51]. T. denticola binds to
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L. Yousefi, et al. Microbial Pathogenesis 144 (2020) 104193
fibroblasts by two ways: lectin-like adhesion on its surface that has By activation CD14 through TLR4-dependent pathway, monocytes
affinity to mannose and galactose on fibroblast surface and a factor and endothelial cells are activated and release pro-inflammatory mo-
present in host serum binding the bacterium to fibroblasts [52]. lecules including Interleukin 1 (IL-1), tumor necrosis factor (TNF),
Prostaglandin E2 (PGE2) and IL-6. These molecules produce in-
2.1.3.1. OppA protein. OppA protein is a 70 or 72 KDa protein that is flammatory mediators such as histamine and prostaglandins [69].
located in T.denticola surface and serves as an adhesion. This protein Studies have shown that in periodontal diseases level of CD14 is in-
has a role in interaction between the organism and host tissue in creased due to presence of LPS in blood circulation [70].
periodontitis [53]. An investigation has found that it is involved in
binding the organism to soluble proteins not to receptors on host cells 2.1.6. Toxins and enzymes
[54]. OppA was present in representative strains of T. denticola and in Spirochetes contain enzymes or substances that directly damage to
T.vincentii but was not detected in T. pectinovorum or T.socranskii [54]. tissue. Oral spirochetes in periodontal diseases release toxic substances
Binding of soluble host proteins by OppA may be important both for and enzymes that are important in development of periodontitis. These
spirochete-host interactions in the subgingival environment and for products damage to tissue by activating immune responses [71]. This
uptake of peptide nutrients. organisms have different proteolytic enzymes like collagenolytic en-
zyme. T. denticola, T. vincentii, and the unspeciated strain, contain
2.1.3.2. Major surface protein. Major surface protein (MSP) is involved collagenolytic enzymes. T. denticola contains a fibrinolytic enzyme and
in interaction between the organism the host cells, and so play a role in peptidases for hydrolyzing synthetic trypsin substrates [72]. Surface
periodontal disease [55]. MSP control the attachment and also and secreted enzymes of T. denticola are as virulence factors. One of
cytopathic effects of the bacterium on host cells and is like porins these is serine protease that has chymotrypsin-like activity [73].
that has pore-forming activity [56]. In cell membrane of the bacterium, Synthesis and secretion of phosphatidylcholine-hydrolyzing phos-
this protein has oligomeric form and is homologous to Tpr proteins in T. pholipase C (PLC) by T. denticola, T. vincentii, and T. phagedenis has been
pallidum subsp. Pallidum, which reacts with antibody during syphilis. investigated. The assay for PLC activity is based on the hydrolysis of p-
Has been reported that MSP can mediate the adhesion to extracellular nitrophenylphosphorylcholine (NPPC) with producing the chromogen,
matrix (ECM) components that causes secretion of proteinase from p-nitrophenol (NP) [74]. T. denticola contains a trypsin-like enzyme that
polymorphonuclear leukocytes (PMLs) and regulates pro-inflammatory can be identified by the hydrolysis of benzoyl-DL-arginine-2-naphthy-
cytokines in various cells. In the outer membrane of the bacterium, MSP lamide (BANA). This enzyme could also be identified in subgingival
combines with chymotrypsin-like protein (CTLP) and this complex has plaque and was associated to the plaque levels and proportions of
molecular mass of about 150 kDa [56]. Sequencing of Msp of T. spirochetes [75]. A, BANA-positive plaque shows about 30% spir-
maltophilum and T. lecithinolyticum has determined that probably it has ochetes in subgingival plaque. Ability of subgingival plaque for hy-
role in adherence as well as Msp in T. denticola [57]. Msp and CTLP are drolyzing BANA is a reliable sign for presence of high proportions of
important in nutrient acquisition in these bacteria. Also, Msp prevent spirochetes and could be used clinically to identify those sites and in-
the cell from degradation by presenting CTLP on its surface [58]. dividuals who require treatment for reduction of spirochetal over-
growth [75]. T. denticola contains enzymes that can degrade peptides.
2.1.4. Colonization Two of these enzymes catalyze the hydrolysis of substrates that have
Adherence plays an important role in cytopathology of oral spir- arginine [76]. Two other peptidases in T. denticola have tendency for
ochetes. T. denticola binds to hydroxyapatite covered with saliva, serum catalyzing proline. This bacterium also is active against phenylalanine
or crevicular fluid. This shows that Treponema can colonizes dental containing substrates and these enzymes aren't very active against na-
hard surfaces like gingival tissue [59]. T. denticola binds to epithelial tive proteins [77]. The organism releases real protease that degrades
cells, fibroblasts and erythrocytes in different sites [60]. Surface and elastin, fibrin, keratin and collagen in basement membrane. Their re-
secreted proteins of T. denticola are necessary in colonization and cy- sults were that T. vincentii has low activity for enzymes but T. denticola
totoxicity and host immunological responses in periodontal diseases has strong activity for N-a-benzoyl-L-arginine-p-nitroanilide (BAPNA)
[61]. These bacteria have interaction with other bacteria especially and succinyl-L-alanyl-L-alanyl-L-prolyl-L-phenylalanine-p-nitroanilide
Fusobacterium spp. Porphyromonas gingivalis and Fusobacterium spp ag- (SAAPNA) [78]. They degraded N-acetyl-tyrosine-p-nitroanilide very
gregate with T. denticola in order to facilitate colonization [62,63]. little and did not degrade other synthetic substrates. The enzyme de-
Coaggregating of P. gingivalis and T. denticola shows that they have graded azocasein and azocoll but not rhemazo brilliant blue elastin
symbiotic life. When they are cultured with each other, P. gingivalis [79]. The chymotrypsinlike enzyme is a real protease because it de-
presumably produces glycine and thiamin for T. denticola, this has been grades different proteins like immunoglobulin A, immunoglobulin G,
understood from expression of their genes in culturing them alone [58]. α1-antitrypsin, BSA, transferrin, gelatin and fibrinogen, and it cleavages
polypeptides in one or several sites. T. denticola has also been reported
2.1.5. Lipopolysaccharides to has enzymes for degrading chondroitin sulfate and hyaluronic acid
Lipopolysaccharides (LPS), also known as lipoglycans and en- that are kinds of glycosaminoglycans [79]. Dentilisin, another enzyme,
dotoxins, are large molecules consisting of a lipid and a polysaccharide has a role in degradation of miscellaneous proteins like fibronectin,
composed of O-antigen, outer core and inner core joined by a covalent laminin and type IV collagen and also serum proteins including fi-
bond; they are found in the outer membrane of Gram-negative bacteria brinogen, transferrin, Immunoglobulin A (IgA), IgG and α 1-antitrypsin.
[64]. Lipid A is a portion of LPS in Gram-negative organisms that in- Also, this proteinase contributes to adhesion of organism to epithelial
duces inflammatory response. LPS activates innate immune system by cells. Dentilisin is the most important factor in penetrating of T. denti-
inducing TLR-4, a surface protein for identifying bacterial products cola to tissue. It has been shown that dentilisin activates host pro-
[65]. As LPS comes into blood circulation, it causes several biological collagennases and so, host enzymes presumably cooperate with T.
reactions such as fever, shock, intravascular coagulation. Concentration denticola in tissue degradation [80].
of LPS in serum is increased in periodontal diseases and causes systemic
complications [66]. LPS has a notable effect on most of cells in peri- 2.1.7. Transporting metals
odontal tissue compromising macrophages, lymphocytes, fibroblasts Most bacteria for acquiring iron release siderophores, that get iron
and osteoclasts. Most of the pathogenesis of periodontal diseases is from host proteins and after interaction with receptors on bacterial
associated to biological activity of LPS [67]. LPS binds to its receptor, membranes transfer iron [81]. Also, some organisms have outer mem-
cluster of differentiation-14 (CD14) in membrane of monocytes/mac- brane proteins that are induced during low iron, bind to transferrin and
rophages, via LPS binding protein (LBP) [68]. lactoferrin for getting iron. At last, some gram negative bacteria provide
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L. Yousefi, et al. Microbial Pathogenesis 144 (2020) 104193
their required iron from compounds containing heme [82]. T.denticola crevicular epithelial cells or producing of arachidonic acid that is used
does not secret siderophores, it can attach lactoferrin and haemin and in the production of prostaglandins and leukotrienes. The eicosanoids
also lyses erythrocytes by hemolysin for causing heme compounds [83]. are agent of inflammation, destroy of tooth attachment and bone lose
T.denticola has two haemin binding proteins, a 47-kDa from strain [97].
ATCC 35405 [84] and a 44-kDa from strains GM-1, MS-25, ATCC T. denticola can cancel oxidative burst of neutrophils in vitro. Some
33520, and ATCC 33404, but their role in iron acquisition have not strains of T. denticola prevented lymphocyte that was acting against
been confirmed and their mechanisms have not been determined [85]. phytohemagglutinin, phorbol myristate acetate, concanavalin A and
Table- 2 shows summary of virulence factors of T. denticola. antigen SKSD [98]. The inhibition was dependent on the presence of
monocytes and it is possible to reverse by using catalase and in-
2.2. Host tissue responses and immunological interactions domethacin, showing that hydrogen peroxide and prostaglandins had
role as mediators. T. denticola prevent from proliferation of fibroblast by
Toxic substances and enzymes released from oral spirochetes da- a cell-bound factor with about 50000 molecular weight [99]. Some
mage to tissue by activating immune responses [86]. Spirochetes by strains of T. denticola suppress growing of fibroblast without affecting
increasing their number cause inflammation. They have endotoxin and on cell viability. If these bacteria do in vivo like in vitro, they could
this endotoxin is present in subgingival plaque. Their small size and change fibroblast proliferation and involve in normal tissue home-
motility are factors of invading to periodontal tissues and at this site ostasis. These findings show that endotoxin do not interfere in inhibi-
release their endotoxin near to fibroblasts and epithelial cells [87]. The tion [7]. T. denticola shows keratinolytic activity in tissue culture by
most important host defense cells are polymorphonuclear leukocytes binding to epithelial cells. If any of these enzymes and factors release in
(PMNs), so their functions like chemotaxis, enzyme secretion and subgingival environment, can have contact with host tissue and cells
phagocytosis have been investigated. Obviously, phagocytes after in- and this contact is increased by penetrating the organisms into epi-
teracting with bacteria by releasing free radicals kill ingested micro- thelial spaces and inside connective tissue and this ability, especially for
organisms [88]. In PMNs oxygen consumption increases with hap- T. denticola, causes to prevent PML function. Invading to host causes
pening respiratory burst. Nearly 90% of that oxygen use for producing immune system to cross with spirochetal antigens [100]. Has been re-
superoxide free radicals (O2ˉ). O2 alone could not be a bactericidal ported that in individual with moderate periodontitis there is high titers
agent, O2ˉ is origin of hydrogen peroxide (H202). Phagocytes destroy of antibodies against spirochetes but about individuals with severe
bacteria by H202 and its metabolites [89]. T. denticola and T. vincentii disease have not been reported. In a study have been found that both
prevent from polymorphonuclear Leukocyte (PMNL) function invitro healthy and periodontitis patients have high titers of antibody against
and thus could not be phagocyted [90]. Simultaneously, lysosomal T. denticola, T. vincentii, and T. phagedenis [99]. In another survey, same
granules aren't degranulated and suggest that fusion of lysosomes with people with the most severe periodontitis showed a lower antibody ti-
phagosomes might be limited. Degranulation decreases by zymosan ters to T. denticola and T. socranskii compared with people with less
when PMNs accost with spirochetes [91]. periodontal morbidity and healthy controls. These findings show that
In various forms of periodontitis the chemotactic characteristic of spirochetes are immunogenicity, but did not use from antigens that
crevicular fluid polymorphonuclear neutrophils (CF-PMN) has been identify diagnostic antibody response. Alternately, in presence of high
investigated. Most of researches have showed that neutrophils reduce antigens, these organisms cause immune suppression and thereby can
their phagocytotic and chemotactic behaviour in early onset period- escape from host immune system [99].
ontitis [92]. It is not fully obvious whether chemotactic disorders
happen in early or late stages of infection. Cytokines function has been 3. Conclusion
surveyed in periodontitis patients. Specially, TNF-a and IL-1 in site of
infection increase. These cytokines have immunomodulatory impacts Spirochetes specially T. denticola play notable role in periodontal
on immune cells and also nonimmune cells consist of PMNs, so they diseases and also are prevalent in other oral infections. Periodontitis
could prevent from chemotaxis of PMNs and lower N-formyl-methionyl influences on risk of systemic diseases such as artherovascular, rheu-
peptides (fMLP) receptors [92]. Immunoregulatory mechanisms matoid arthritis and some kinds of cancers. So this review has analysed
monitor Leukocytes and their products, and severity of the periodontitis mechanisms of pathogenesis of oral spirochetes in periodontitis and
depends on inflammatory response and biofilm. In Periodontitis lesions oral infections, therefore it will help us to significantly treat these
there are a lot of leukocytes and among them plasma cells are pre- diseases. The review of the included articles has showed that oral
dominant cells- accompanied by lymphocytes form almost 75–80% of spirochetes established infections and periodontitis by its virulence
inflammatory cells [93]. factors. There is a need for more studies investigating the known me-
B cells are a part of adaptive immune system. It's mechanism include chanisms of pathogenesis in oral infections and periodontitis associated
converting into plasma cells and generating antibodies. B cells have with oral spirochetes. In addition, this study has not shown all of genes
immuno-regulatory importance consist of direct and indirect influence encoding virulence factors of related bacteria. Future reviews might
on other cells by antigen presentation and releasing cytokines [94]. provide further insight into the understanding of the disease, as well as
Plasma cells generate cytokines like TNF-α, IL-6, IL-10 and TGF-β. TNF- new possible mechanisms to eliminate oral spirochetes in primary in-
α through stimulating matrix metalloproteinases (MMPs) increases fections.
extracellular matrix, but TGF-β reduce production of these MMPs [95].
Plasma cells located near blood vessels induce vascular endothelial
Declaration of competing interest
growth factor, that activate MMPs. So, plasma cells are a lot in the
inflammation site and MMP-mediated tissue degradation is obvious.
MMP-mediated tissue destruction have been studied in oral diseases. None to declare.
So, MMP is active in gingivitis and is related to periodontitis [96].
MMPs are released by neutrophils and fibroblasts and support de- Acknowledgment
gradation of collagen. MMP-8 and MMP-13 (collagenases 2 and 3) were
also produced by macrophage-like cells and plasma cells [96]. PLC This study was supported by Faculty of Medicine, Tabriz University
secreted by T. denticola, T. vincentii, and T. phagedenis has ability of of Medical Sciences with reference number 63656 and ethic committee
hydrolyzing membrane phospholipids and this results in destruction of approved with registration number IR.TBZMED.REC.1398.1003.
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