Pathogenesis and Clinical manifestation of Gardenerella vaginalis

Gardenerella vaginalis is a gram-variable bacterium that is commonly associated with bacterial vaginosis (BV), a condition characterized by an imbalance of the normal vaginal flora and a malodorous discharge. BV affects millions of women worldwide and is associated with increased risk of sexually transmitted infections, pelvic inflammatory disease, preterm birth, and other adverse outcomes. The pathogenesis of G. vaginalis is complex and involves multiple factors that enable the bacterium to adhere to the host epithelium, produce cytotoxic substances, form biofilms, and alter the vaginal environment. In this article, we will review the current knowledge on the mechanisms of infection by G. vaginalis and its clinical manifestations.

One of the key factors that determine the pathogenicity of G. vaginalis is its ability to adhere to the host epithelial cells that line the vaginal mucosa. This is the first step in establishing infection and colonization by the bacterium. Adherence is mediated by several mechanisms, including:

• Vaginolysin: This is a cholesterol-dependent cytolysin (CDC) that is produced by G. vaginalis and binds to the CD59 molecule on the surface of human cells. CD59 is a complement regulatory protein that protects cells from complement-mediated lysis. By binding to CD59, vaginolysin disrupts the membrane integrity of the host cells and causes cell death. Vaginolysin also facilitates the adherence of G. vaginalis to the host cells by exposing the underlying receptors for bacterial attachment.
• Pore-forming toxin: This is another CDC that is encoded by G. vaginalis and has a similar mode of action as vaginolysin. It also binds to CD59 and forms pores on the cell membrane, leading to cell lysis and adherence.
• Cytotoxin: This is a protein that is secreted by G. vaginalis and has a specific toxicity for human cells. It induces apoptosis (programmed cell death) in the host cells by activating caspases, which are enzymes that trigger a cascade of events leading to cell death. Cytotoxin also enhances the adherence of G. vaginalis to the host cells by increasing the expression of integrins, which are receptors for bacterial attachment.

These cytotoxic substances not only damage the host cells, but also create an inflammatory response in the vaginal mucosa, which further contributes to the pathogenesis of G. vaginalis. The inflammation attracts immune cells, such as neutrophils and macrophages, which release reactive oxygen species (ROS) and cytokines that cause tissue damage and alter the vaginal microenvironment.

The adherence of G. vaginalis to the host epithelium is also influenced by the presence or absence of lactobacilli, which are the predominant bacteria in a healthy vagina. Lactobacilli produce lactic acid and hydrogen peroxide, which lower the pH and inhibit the growth of G. vaginalis and other pathogens. However, some strains of G. vaginalis have been shown to have a greater capacity to adhere to epithelial cells in the presence of Lactobacillus crispatus, which is one of the most common species of lactobacilli in the vagina. This may be due to the fact that L. crispatus produces a surface protein called S-layer, which may act as a receptor for G. vaginalis attachment.

The adherence of G. vaginalis to the host epithelium is a crucial step in initiating infection and setting the stage for subsequent biofilm formation and symbiosis with anaerobes, which are discussed in later points.

One of the cytotoxic substances that G. vaginalis produces is vaginolysin, a cholesterol-dependent cytolysin that targets human cells. Vaginolysin is a protein that forms pores on the cell membrane of the host epithelium, causing cell lysis and tissue damage. Vaginolysin also has immunomodulatory effects, such as inducing cytokine release, activating complement, and inhibiting phagocytosis.

Another cytotoxin that G. vaginalis encodes is a pore-forming toxin that binds to the CD59 human complement regulatory molecule. CD59 is a glycosylphosphatidylinositol-anchored protein that protects host cells from complement-mediated lysis by preventing the formation of the membrane attack complex. By binding to CD59, the pore-forming toxin disrupts its function and makes the host cells more susceptible to complement-mediated damage.

The production of vaginolysin and pore-forming toxin by G. vaginalis may facilitate its initial adherence to the host epithelium, as well as its invasion and colonization of the vaginal mucosa. These cytotoxins may also contribute to the inflammation and symptoms associated with bacterial vaginosis, such as vaginal discharge, odor, and irritation.

One of the key factors that contribute to the pathogenicity of G. vaginalis is the production of vaginolysin, a cholesterol-dependent cytolysin that targets human cells. Vaginolysin binds to the CD59 molecule on the surface of epithelial cells and forms pores that disrupt the membrane integrity and cause cell lysis. Vaginolysin also induces inflammation and tissue damage by activating the complement system and releasing pro-inflammatory cytokines.

Another important factor that enhances the virulence of G. vaginalis is the ability to form biofilms on the vaginal mucosa. Biofilms are complex communities of bacteria that are embedded in a matrix of extracellular polymeric substances (EPS). Biofilms provide protection from host immune responses, antimicrobial agents, and environmental stress. Biofilms also facilitate the adherence and colonization of other anaerobic bacteria that are associated with bacterial vaginosis.

G. vaginalis produces a cytotoxin that is distinct from vaginolysin and has a different mode of action. The cytotoxin is a protein that binds to the epithelial cells and causes cell rounding, detachment, and death. The cytotoxin also inhibits the growth of lactobacilli, the beneficial bacteria that maintain the normal vaginal flora and pH. The cytotoxin may also interfere with the host defense mechanisms by impairing the phagocytic activity of neutrophils and macrophages.

The combined effects of vaginolysin, biofilm formation, and cytotoxin result in a disruption of the vaginal ecosystem and a shift to a more alkaline and anaerobic environment. This creates favorable conditions for the overgrowth of G. vaginalis and other pathogenic bacteria that cause bacterial vaginosis.

Lactobacillus crispatus is one of the dominant species of lactobacilli that colonize the healthy human vagina. It produces lactic acid and hydrogen peroxide, which create an acidic and oxidative environment that inhibits the growth of pathogenic bacteria. L. crispatus also competes with other bacteria for adhesion sites on the vaginal epithelium, preventing their colonization and invasion.

However, G. vaginalis has the ability to adhere to epithelial cells in the presence of L. crispatus, which may facilitate its infection and persistence in the vagina. Studies have shown that G. vaginalis can bind to mannose receptors on the epithelial cells, which are also used by L. crispatus for adhesion. Moreover, G. vaginalis can produce vaginolysin, a cytotoxin that damages the epithelial cells and reduces their ability to support L. crispatus growth. Vaginolysin also disrupts the tight junctions between epithelial cells, creating gaps that allow G. vaginalis and other bacteria to penetrate deeper into the tissue.

Additionally, G. vaginalis can form biofilms on the epithelial surface, which protect it from the antimicrobial action of lactic acid and hydrogen peroxide. Biofilms also enhance the adherence and aggregation of G. vaginalis and other anaerobic bacteria, creating a synergistic effect that promotes bacterial vaginosis. Furthermore, some strains of G. vaginalis can produce sialidase, an enzyme that cleaves sialic acid residues from mucins and other glycoproteins on the epithelial surface. Sialidase may increase the availability of mannose receptors for G. vaginalis binding, as well as degrade the mucosal barrier that prevents bacterial invasion.

Therefore, G. vaginalis has several mechanisms to overcome the protective role of L. crispatus in the vagina and establish infection. The adherence of G. vaginalis in the presence of L. crispatus is a crucial step in the pathogenesis of bacterial vaginosis.

G. vaginalis is a gram-variable bacterium that can adhere to the vaginal epithelium and form biofilms. Biofilms are communities of bacteria that are embedded in a matrix of extracellular polymeric substances (EPS) and are resistant to host defenses and antimicrobial agents. Biofilms also facilitate the exchange of genetic material and metabolic products among bacteria, creating a favorable environment for the growth of other anaerobic bacteria.

G. vaginalis produces several virulence factors that contribute to its pathogenesis. One of them is vaginolysin, a pore-forming toxin that binds to the CD59 molecule on human cells and causes cell lysis and inflammation. Vaginolysin also disrupts the epithelial barrier and allows the translocation of other bacteria into the subepithelial tissue. Another virulence factor is sialidase, an enzyme that cleaves sialic acid residues from mucins and other glycoproteins. Sialidase enhances the adherence of G. vaginalis to the epithelium and promotes biofilm formation by exposing the underlying carbohydrate structures. Sialidase also increases the availability of sialic acid as a nutrient source for G. vaginalis and other bacteria.

G. vaginalis can alter the vaginal microbiota and pH by producing ammonia and other metabolites that inhibit the growth of lactobacilli, the predominant bacteria in the healthy vagina. Lactobacilli produce lactic acid and hydrogen peroxide, which maintain a low pH and prevent the overgrowth of pathogenic bacteria. G. vaginalis can degrade lactic acid and hydrogen peroxide and neutralize their antimicrobial effects. G. vaginalis can also establish a symbiotic relationship with other anaerobic bacteria, such as Prevotella bivia, that use amino acids as their energy source and produce ammonia as a by-product. Ammonia increases the pH and creates a more alkaline environment that favors the growth of G. vaginalis and other anaerobes.

The overgrowth of G. vaginalis and other anaerobic bacteria leads to bacterial vaginosis (BV), a common vaginal infection characterized by a thin, grayish-white discharge with a fishy odor, itching, burning, and inflammation. BV is associated with increased risks of preterm birth, pelvic inflammatory disease, sexually transmitted infections, and HIV acquisition.

Biofilm is a complex community of microorganisms that adhere to a surface and are embedded in a matrix of extracellular polymeric substances. Biofilm formation is a common strategy for bacterial survival and persistence in various environments, including the human body. Biofilm production confers several advantages to the bacteria, such as protection from host immune responses, antimicrobial agents, environmental stress, and predation. Biofilm also facilitates nutrient acquisition, gene transfer, and quorum sensing among the bacterial population.

G. vaginalis is one of the main biofilm-forming bacteria in the vagina. It has been shown that biofilm production is critical for the survival of G. vaginalis in the vagina, especially in the presence of lactobacilli, which are the dominant and beneficial bacteria in the normal vaginal flora. Lactobacilli produce lactic acid and hydrogen peroxide, which lower the vaginal pH and create an acidic and oxidative environment that inhibits the growth of pathogenic bacteria. However, G. vaginalis biofilms are tolerant to lactic acid and hydrogen peroxide, and can resist the antimicrobial activity of lactobacilli.

G. vaginalis biofilms also enhance the adherence of G. vaginalis to the vaginal epithelium, which is the initial step for infection and invasion. Moreover, G. vaginalis biofilms promote the colonization and growth of other anaerobic bacteria that are associated with bacterial vaginosis, such as Prevotella, Mobiluncus, and Atopobium. These bacteria can coexist within the same biofilm or form separate biofilms that interact with each other. The presence of multiple bacterial species in the biofilm increases the diversity and complexity of the microbial community, which may contribute to the pathogenesis and persistence of bacterial vaginosis.

Therefore, biofilm production is an important virulence factor for G. vaginalis that enables it to survive and thrive in the vagina, despite the presence of lactobacilli and other host defenses. Biofilm production also facilitates the establishment and maintenance of bacterial vaginosis by creating a favorable environment for G. vaginalis and other anaerobic bacteria.

Sialidase is an enzyme that cleaves sialic acid residues from glycoproteins and glycolipids. Sialic acid is a component of mucin, which is a protective layer of mucus that covers the epithelial cells of the vagina. Sialidase is produced by some strains of G. vaginalis and may play a role in enhancing biofilm production by G. vaginalis.

Biofilm is a complex community of bacteria that adhere to a surface and are embedded in a matrix of extracellular polymeric substances (EPS). Biofilm formation is a critical virulence factor of G. vaginalis, as it protects the bacteria from host immune responses, antimicrobial agents, and environmental stresses. Biofilm formation also facilitates the colonization and growth of other anaerobic bacteria that are associated with bacterial vaginosis.

Sialidase may enhance biofilm production by G. vaginalis through its mucinase activity. By cleaving sialic acid from mucin, sialidase may disrupt the integrity and function of the mucosal barrier, exposing the epithelial cells to bacterial adherence and invasion. Sialidase may also release sialic acid as a nutrient source for G. vaginalis and other bacteria in the biofilm. Furthermore, sialidase may modify the EPS matrix of the biofilm, making it more stable and resistant to degradation.

Sialidase activity has been correlated with biofilm formation by G. vaginalis in vitro and in vivo studies. In vitro studies have shown that sialidase-positive strains of G. vaginalis form more robust biofilms than sialidase-negative strains on various substrates, such as glass, plastic, and human epithelial cells. In vivo studies have shown that sialidase-positive strains of G. vaginalis are more prevalent and abundant in women with bacterial vaginosis than in women with normal vaginal flora.

Sialidase may also contribute to the pathogenesis of bacterial vaginosis by altering the vaginal microbiota and pH. Sialidase may reduce the number and activity of lactobacilli, which are the predominant bacteria in the normal vaginal flora and produce lactic acid and hydrogen peroxide to maintain a low pH and inhibit the growth of pathogenic bacteria. Sialidase may also increase the pH of the vagina by releasing ammonia from sialic acid degradation, creating a favorable environment for G. vaginalis and other anaerobes.

Therefore, sialidase is an important enzyme that may enhance biofilm production by G. vaginalis and contribute to the pathogenesis of bacterial vaginosis.

One of the main factors that maintain the normal vaginal flora is the production of lactic acid and hydrogen peroxide by lactobacilli. These substances lower the pH of the vagina and inhibit the growth of pathogens such as G. vaginalis . However, G. vaginalis can overcome this hostile environment by forming biofilms on the vaginal epithelium . Biofilms are complex communities of bacteria that are embedded in a matrix of extracellular polymeric substances (EPS). Biofilms provide protection to bacteria from antimicrobial agents, host immune responses, and environmental stresses.

G. vaginalis biofilms have been shown to be more resistant to lactic acid and hydrogen peroxide than planktonic (free-floating) cells. The mechanisms of this resistance are not fully understood, but some possible explanations are:

• The EPS matrix may act as a physical barrier that prevents or reduces the diffusion of lactic acid and hydrogen peroxide into the biofilm.
• The EPS matrix may also bind or neutralize lactic acid and hydrogen peroxide, reducing their effective concentrations.
• The biofilm bacteria may express different genes or proteins that enhance their tolerance to lactic acid and hydrogen peroxide. For example, some strains of G. vaginalis produce sialidase, which can degrade mucin and increase the production of EPS .
• The biofilm bacteria may cooperate with each other or with other anaerobes to modulate the pH or scavenge reactive oxygen species .

The tolerance of G. vaginalis biofilms to lactic acid and hydrogen peroxide is one of the factors that contribute to its persistence and virulence in the vagina. It also poses a challenge for the treatment and prevention of BV, as conventional antibiotics may not be able to penetrate or eradicate the biofilm. Therefore, new strategies that target the biofilm phenotype of G. vaginalis are needed to improve the management of BV.

One of the hallmarks of BV is the presence of a polymicrobial community of anaerobic bacteria that replace the normal lactobacilli in the vagina. Among these anaerobes, Prevotella, Mobiluncus, Peptostreptococcus, and Bacteroides species are frequently detected . However, these bacteria are not always pathogenic by themselves and may require the presence of G. vaginalis to initiate or sustain BV.

G. vaginalis has been shown to have a symbiotic relationship with some of the strict anaerobes in BV. For example, Prevotella bivia, a common BV-associated bacterium, can use amino acids produced by G. vaginalis as its fuel source and in turn produce ammonia, which can be used by G. vaginalis . Ammonia also contributes to the alkalization of the vaginal pH, which favors the growth of anaerobes and inhibits lactobacilli .

Another way that G. vaginalis may enhance the growth of anaerobes is by forming biofilms on the vaginal epithelium. Biofilms are complex structures of bacteria embedded in a matrix of extracellular polymeric substances that protect them from host defenses and antimicrobial agents . G. vaginalis is considered to be the primary biofilm-forming bacterium in BV and may facilitate the adherence and colonization of other anaerobes within the biofilm .

Therefore, G. vaginalis may play a key role in the pathogenesis of BV by establishing a symbiotic relationship with strict anaerobes that leads to a shift in the vaginal microbiota and pH. This relationship may also explain why some women have asymptomatic colonization by G. vaginalis without developing BV, as the presence of other factors such as sexual activity, hormonal changes, or host immunity may influence the balance between G. vaginalis and anaerobes .

One of the consequences of the symbiotic relationship between G. vaginalis and strict anaerobes is the production of ammonia, which can alter the vaginal pH and create a more favorable environment for bacterial vaginosis. Ammonia is a weak base that can react with water to form ammonium hydroxide, which increases the concentration of hydroxide ions and raises the pH.

The main source of ammonia in the vagina is the metabolism of amino acids by proteolytic bacteria, such as Prevotella bivia and G. vaginalis. These bacteria can break down proteins into amino acids and then deaminate them to release ammonia. The amino acids can also be used as an energy source by some anaerobes, such as P. bivia, which can further enhance their growth and colonization.

The normal vaginal pH ranges from 3.8 to 4.5, which is maintained by the production of lactic acid by lactobacilli. Lactic acid is a weak acid that can dissociate into lactate and hydrogen ions, which lower the pH. Lactobacilli also produce hydrogen peroxide, which can inhibit the growth of other bacteria and prevent biofilm formation.

However, when G. vaginalis and other anaerobes overgrow in the vagina, they can reduce the number and activity of lactobacilli and decrease the production of lactic acid and hydrogen peroxide. This can result in a loss of the acidic protective barrier and an increase in the vaginal pH to above 4.5, which is diagnostic of bacterial vaginosis.

A higher pH can also affect the host immune response and increase the susceptibility to other infections, such as sexually transmitted diseases and pelvic inflammatory disease. Moreover, a higher pH can enhance the expression of virulence factors by G. vaginalis, such as vaginolysin and sialidase, which can further damage the host epithelium and facilitate biofilm formation.

Therefore, ammonia production by G. vaginalis and other anaerobes is a key factor in the pathogenesis of bacterial vaginosis, as it shifts the vaginal pH to a more alkaline level and creates a vicious cycle of bacterial overgrowth, inflammation, and tissue damage.

Bacterial vaginosis (BV) is a common vaginal condition that occurs when the normal balance of bacteria in the vagina is disrupted by the overgrowth of certain bacteria, especially G. vaginalis and other anaerobes . BV can cause symptoms such as thin, gray, white or green vaginal discharge, foul-smelling \"fishy\" vaginal odor, vaginal itching, and burning during urination . However, many women with BV have no signs or symptoms .

BV can increase the risk of getting or transmitting sexually transmitted diseases (STDs), such as chlamydia, gonorrhea, herpes, and HIV. BV can also cause complications during pregnancy, such as preterm birth, low birth weight, and increased risk of infection after delivery .

The exact cause of BV is not fully understood, but it is associated with factors that alter the vaginal flora, such as having multiple or new sex partners, douching, using intrauterine devices (IUDs), and having a natural lack of lactobacilli bacteria . BV is not a sexually transmitted infection (STI), but it can be spread through sexual contact between female partners.

The diagnosis of BV is based on the clinical signs and symptoms, as well as the microscopic examination of the vaginal fluid for the presence of clue cells (epithelial cells coated with bacteria), which indicate a high concentration of G. vaginalis and other anaerobes . The treatment of BV involves antibiotics, such as metronidazole or clindamycin, which can be taken orally or applied vaginally . The treatment can cure the infection and reduce the symptoms, but it does not prevent recurrence . Therefore, it is important to follow the prevention measures, such as limiting the number of sex partners, using condoms, avoiding douching, and maintaining good hygiene .

BV is a common and treatable condition that affects many women of reproductive age. However, it can have serious consequences for the health of women and their babies if left untreated. Therefore, it is advisable to seek medical attention if you have any signs or symptoms of BV or if you are pregnant or planning to become pregnant.

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