Porphyromonas gingivalis
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''Porphyromonas gingivalis'' belongs to the phylum '' Bacteroidota'' and is a nonmotile,
Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...
, rod-shaped,
anaerobic Anaerobic means "living, active, occurring, or existing in the absence of free oxygen", as opposed to aerobic which means "living, active, or occurring only in the presence of oxygen." Anaerobic may also refer to: * Anaerobic adhesive, a bonding a ...
,
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
ic
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...
. It forms black colonies on blood agar. It is found in the oral cavity, where it is implicated in
periodontal disease Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
, as well as in the upper gastrointestinal tract, the respiratory tract and the colon. It has been isolated from women with
bacterial vaginosis Bacterial vaginosis (BV) is a disease of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urination ...
. Collagen degradation observed in chronic periodontal disease results in part from the
collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
enzymes of this
species In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
. It has been shown in an ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
'' study that ''P. gingivalis'' can invade
human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...
gingiva The gums or gingiva (plural: ''gingivae'') consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health. Structure The gums are part of the soft tissue lin ...
l
fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
and can survive in the presence of antibiotics. ''P. gingivalis'' invades gingival
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
s in high numbers, in which case both bacteria and epithelial cells survive for extended periods of time. High levels of specific antibodies can be detected in patients harboring ''P. gingivalis''. ''P. gingivalis'' infection has been linked to Alzheimer's disease and
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
. It contains the enzyme peptidyl-arginine deiminase, which is involved in citrullination. Patients with
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
have increased incidence of periodontal disease; antibodies against the bacterium are significantly more common in these patients. ''P. gingivalis'' is divided into K- serotypes based upon capsular antigenicity of the various types. These serotypes have been the drivers of observations regarding bacterial cell to cell interactions to the associated serotype-dependent immune response and risk with pancreatic cancer.


Genome

The genome of ''P. gingivalis w''as described in 2003 revealing 1,990
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
s (i.e. protein-coding sequences), encoded by 2,343,479 bp, with an average G+C content of 48.3%. An estimated 463 genes are essential.


Virulence factors


Gingipain

Arg-gingipain (Rgp) and lys-gingipain (Kgp) are
endopeptidase Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this ...
enzymes secreted by ''P. gingivalis.'' These gingipains serve many functions for the organism, contributing to its survival and virulence. Arg-gingipains have been found to play a key role in the collection of nutrients for ''P. gingivalis'' survival. Rgp degrades large peptides of the host organism to provide the bacterium with an abundant nitrogen and carbon source from human albumin serum. ''P. gingivalis'' can also degrade
transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...
within host cells which provides the organism with an abundant iron source needed to perform multiple cellular functions. The gingipains are also responsible for a number of necessary functions related to host invasion and colonization. Rgp gingipains are necessary for adhesion and invasion as they processed precursor proteins of long fimbriae. The ''P. gingivalis'' genes encoding RgpA, Kgp, and hemagglutinin A (HagA) were strongly expressed after incubation with ''T. denticola''. The hemagglutinin adhesion domain-containing proteins act to increase adhesive capacities of ''P. gingivalis'' with other bacterial species. They are also associated with coordinating the integrity of the biofilm in the developing and maturation phase. Lys- gingipains (Kgp) can bind to immobilized matrix proteins
fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
and
fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
and may have a role in host colonization. Gingipains also have the ability to degrade multiple signals of the host immune response. They have the ability to cleave subclass 1 and 3
IgG antibodies Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
as well as proinflammatory cytokines such as IL-1β, IL-2, IL-6, TNF-α and IL-8 in regions of high ''P. gingivalis'' concentration, impairing host immune response function. Rgp can inhibit IL-2 accumulation in
T-cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
, which enables it to evade the host adaptive immune response, by modulating T-cell communication and proliferation. Gingipains are key factors in tissue damage symptoms of
periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...
, which results from the degradation of matrix metalloproteins, collagen, and
fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
. Degradation of these substrates interferes with interactions between host cells and the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
, therefore impeding wound healing and causing destruction of periodontal tissues. Rgp is responsible for eliciting the host inflammatory response via the p38α
MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
transduction pathway. This response likely contributes to the inflammatory nature of periodontitis and is involved in tissue and bone destruction. Gingipains have been associated with Alzheimer's disease (AD). Gingipains were discovered from TMAs of patients exhibiting AD brain pathology. Both RgpB and Kbp were discovered from
hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
and
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...
of AD patients and were found to be associated with
tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...
load, a marker for AD pathology and
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
, which accumulates in tau tangles and amyloid beta plaques in AD brain. ''P. gingivalis'' 16S rRNA was also discovered in the cerebral cortex and csf of AD brains. Pretreatment with gingipain inhibitors protected neuron cell degradation caused by administration of gingipains in murine model.


Capsular polysaccharide (CPS)

The encapsulated strain of ''P. gingivalis'' is much more virulent than the nonencapsulated strain in a mouse abscess model. The capsule is a capsular polysaccharide and when present down regulates
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
production especially proinflammatory cytokines IL-1β, IL-6, IL-8, and
TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, indicating host evasion responses. However, other studies have found the CPS to elicit host immune responses like PMN migration and dose and time dependent expression of cell migration
chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
like MCP-1, KC, MIP-2 and RANTES in CPS-challenged murine peritoneal macrophages. These conditions are likely to contribute to the inflammatory lesions observed in
periodontitis Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main cau ...
. Vaccines made from ''P. gingivalis'' CPS apparently impair oral bone loss in murine models. These vaccines have been able to elicit potent immune responses such as increased
IgM Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
and
IgG Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
responses that recognize whole ''P. gingivalis'' organisms.


Fimbriae

Fimbriae are appendages involved in cellular attachment and greatly contribute to virulence and are found on many Gram-negative and some Gram-positive bacteria. ''P. gingivalis'' virulence is heavily associated with fimbriae as they have been characterized to be key factors in adhesion, invasion, and colonization. Fimbriae are also responsible for invasion of membrane vesicles into host cells. They were found to bind to cellular α5β1
integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
, which mediated adherence and impaired the homeostatic controls of host cells. Fimbriae were also found to be associated with modulating β2 integrin adhesive activity for uptake by monocytes using the
CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). ...
/
TLR2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...
/
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
signaling complex, which may contribute to intracellular evasion tactics by ''P. gingivalis''. ''P. gingivalis'' has long fimbriae, short fimbriae, and accessory components, each of which have distinct functions.


Long fimbriae

Long fimbriae (FimA), also known as major fimbriae, are long, peritrichous, filamentous components. They have a role in initial attachment and organization of biofilms, as they act as adhesins that mediate invasion and colonization of host cells contributing to ''P. gingivalis'' virulence.


Short fimbriae

Short fimbriae (Mfa1), also known as minor fimbriae, have distinct roles from long fimbriae and are characterized to be essential for cell-cell auto aggregation and recruitment for microcolony formation. Short fimbriae are involved in cell-cell adhesion with other dental commensals. It was found to and develop biofilm in conjunction with ''
Streptococcus gordonii ''Streptococcus gordonii'' is a Gram-positive bacterium included among some of the initial colonizers of the periodontal environment. The organism, along with related oral streptococci, has a high affinity for molecules in the salivary pellicle ...
'' by interaction with SspB streptococcal surface polypeptide. This interaction may be essential in the invasion of dentinal tubules by ''P. gingivalis''.


Accessory fimbriae

Fim C, D, and E accessory components associate with the main FimA protein and have a role in binding with matrix proteins and interaction with CXC-chemokine receptor 4. Loss of function experiments have confirmed that ''P. gingivalis'' mutants deficient for Fim C, D, or E have drastically attenuated virulence.


Evasion of host defenses and immune responses

''P. gingivalis'' has many ways of evading host immune responses which affects its virulence. It does this by using a combination of gingipain proteases, a capsular polysaccharide, induction of host cell proliferation, and the cleavage of chemokines responsible for neutrophil recruitment. Virulent ''P. gingivalis'' further modulates leukocyte recruitment by proteolysis of cytokines and
chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
that are secreted by the host cells. The arg-gingipain and lys-gingipains are responsible for this proteolysis. In a study using a mouse model, ''P. gingivalis'' was specifically found to down-regulate IL-8 induction, causing delayed
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
recruitment. Prevention of neutrophil recruitment may inhibit the clearance of the bacterium from the site of infection allowing for colonization. ''P. gingivalis'' is able to evade opsonophagocytosis from PMN’s by using Gingipain K (Kgp) to cleave
IgG Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
1 and 3. This further modulates immune response by impairing signaling. Other studies have found that ''P. gingivalis'' can subvert the
complement A complement is something that completes something else. Complement may refer specifically to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-clas ...
pathway through C5αR and C3αR, which modulates the killing capacity of leukocytes, allowing for uncontrolled bacterial growth. ''P. gingivalis'' was also found to inhibit pro inflammatory and antimicrobial responses in human monocytes and mouse macrophages by fimbrial binding to CXCR4, inducing PKA signaling and inhibiting
TLR-2 Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the ''TLR2'' gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune sys ...
-mediated immune response. Once in the host cells, ''P. gingivalis'' is capable of inhibiting apoptosis by modulating the JAK/Stat pathway that controls mitochondrial apoptotic pathways. A proliferative phenotype maybe beneficial to the bacterium as it provides nutrients, impairs host cell signaling, and compromises the integrity of the epithelial cell layer, allowing for invasion and colonization.


Ecology

''P. gingivalis'' plays an important role in the onset of chronic adult periodontitis. Though it is found in low abundance in the oral cavity, it causes a microbial shift of the oral cavity, allowing for uncontrolled growth of the
commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...
microbial community. This leads to periodontitis through the disruption of the host tissue homeostasis and adaptive immune response. After using laser capture microdissection plus qRT-PCR to detect ''P. gingivalis'' in human biopsies, colocalization of ''P. gingivalis'' with CD4+ T cells was observed. However, the infection mechanism of T cells by ''P. gingivalis'' remains unknown. ''P. gingivalis'' has been associated with increasing the virulence of other commensal bacteria in both ''in vivo'' and ''in vitro'' experiments. ''P. gingivalis'' outer membrane vesicles were found to be necessary for the invasion of epithelial cells of ''
Tannerella forsythia ''Tannerella forsythia'' is an anaerobic, Gram-negative bacterial species of the Bacteroidota phylum. It has been implicated in periodontal diseases and is a member of the red complex of periodontal pathogens. ''T. forsythia'' was previously n ...
''. ''P. gingivalis'' short fimbriae were found to be necessary for coculture biofilm formation with ''
Streptococcus gordonii ''Streptococcus gordonii'' is a Gram-positive bacterium included among some of the initial colonizers of the periodontal environment. The organism, along with related oral streptococci, has a high affinity for molecules in the salivary pellicle ...
''. Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving ''P. gingivalis'' and ''
Treponema denticola ''Treponema denticola'' is a Gram-negative, obligate anaerobic, motile and highly proteolytic spirochete bacterium. It is one of four species of oral spirochetes to be reliably cultured, the others being ''Treponema pectinovorum, Treponema socra ...
''. The role of ''P. gingivalis'' in periodontitis is studied using specific pathogen-free mouse models of periodontal infections. In these models, ''P. gingivalis'' inoculation causes significant bone loss, which is a significant characteristic of the disease. In contrast, germ free mice inoculated with a ''P. gingivalis'' monoinfection incur no bone loss, indicating that ''P. gingivalis'' alone cannot induce periodontitis.


See also

*
List of bacterial vaginosis microbiota Bacterial vaginosis is caused by an imbalance of the naturally occurring bacteria in the vagina. The normally predominant species of ''Lactobacilli'' are markedly reduced. This is the list of organisms that are found in the vagina that are assoc ...


References


External links


Type strain of ''Porphyromonas gingivalis'' at Bac''Dive'' – the Bacterial Diversity Metadatabase
{{DEFAULTSORT:Porphyromonas Gingivalis Bacteroidia Inflammatory diseases of female pelvic organs Reproductive system Gynaecology Sexual health Bacterial vaginosis Bacteria described in 1988