Gingipain Arg-gingipain (Rgp) and lys-gingipain (Kgp) are
endopeptidase enzymes secreted by
P. gingivalis through a
type IX secretion system (T9SS). 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 serum albumin.
P. gingivalis can also degrade
transferrin 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. 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 and
fibronectin 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 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, 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, which results from the degradation of
matrix metalloproteins,
collagen, and
fibronectin. The capsule is a capsular polysaccharide and when present down regulates
cytokine production especially proinflammatory
cytokines IL-1β, IL-6, IL-8, and
TNF-α, indicating host evasion responses. Vaccines made from capsular polysaccharide of
P. gingivalis apparently impair oral bone loss in murine models. These vaccines have been able to elicit potent immune responses such as increased
IgM and
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. Fimbriae were also found to be associated with modulating β2 integrin adhesive activity for uptake by
monocytes using the
CD14/
TLR2/
PI3K 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. 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. 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 (
CXCR4). 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 heightens 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 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 recruitment. Prevention of neutrophil recruitment may inhibit the clearance of the bacterium from the site of infection allowing for colonization.
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-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. 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 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.
P. gingivalis short fimbriae were found to be necessary for coculture biofilm formation with
Streptococcus gordonii. 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. and
in vivo studies using a mouse model. It is thought that periodontitis is linked to cardiovascular disease due to
inflammation pathways, which the two pathologies have in common. The inflammation pathway of periodontitis is such that as the infection grows, bacteria, including
P. gingivalis are targeted by neutrophils and natural killer immune cells. These cells phagocytize the bacteria, while simultaneously
cytokine molecules in the area lead to a proinflammatory environment. This proinflammatory environment is also rich in intercellular signaling molecules including
tumor necrosis factor-alpha,
interleukins (
interleukin 1,
interleukin 4,
interleukin 10),
interferons and
transforming growth factor beta. These molecules recruit more enzymes and transcription factors, which then in turn recruit more immune cells, forming a positive feedback loop which can make the immune response, and therefore the inflammation become chronic and systemic. Chronic inflammation of gum tissue can lead to a loss of this tissue and of bone tissue as well. The inflammation upregulates production of
RANKL, an intercellular signaling molecule that promotes bone tissue dissolution, leading to a gradual loss of bony tissue.
P. gingivalis infection is also thought to lead to
oxidative stress. Both chronic systemic inflammation and oxidative stress are factors associated with the onset of cardiovascular disease, and are proposed mechanisms by which periodontal disease may, if it indeed is causationally linked to cardiovascular disease, accelerate the disease process of a cardiovascular disease. While invasive
P. gingivalis is associated with various forms of cardiovascular disease, including
stroke,
coronary artery disease,
atrial fibrillation, and
heart failure, the best evidence of a direct causational link is between invasive
P. gingivalis (periodontal disease) and atherosclerosis. In vivo and in vitro animal models have found that the fimbriae of
P. gingivalis promote host cell entry and
atherothrombotic lesion formation once the bacteria enter the bloodstream, such as through lesions in the mouth.
P. gingivalis has been shown to accelerate the atherosclerosis disease pathway in mice, as well as being found in human atherosclerotic plaque lesions. == See also ==