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In the last decade, there have been quite a lot of scientific advances reported regarding the immunology and pathophysiology of human vaginal microbiota. As a result, physicians have a more comprehensive understanding of the role that lactobacilli exert in the vaginal milieu and their interactions with vaginal mucosa, pathogenic bacteria and fungi. This commentary addresses those advances in vaginal microflora, vaginal epithelial cells, immunity, bacterial vaginosis BV and candidiasis.

Additionally, recent reports regarding lactobacilli biofilm formation will be discussed. Last, an assessment of future implications is presented. Lactobacilli are the most abundant bacteria present in normal vaginas of women of child-bearing age with some exceptions due to race, geographic location and ethnic groups Figure 1.

They are mainly derived from intestinal microbiota. This bacillus was subsequently renamed as Lactobacillus [ 1 ]. This fundamental concept still continues to be utilized today. The vaginal microflora continuously go through modifications regarding the number and type of bacteria present, almost daily, in response to exogenous and endogenous factors [ 2 ]. These factors include the menstrual cycle phases, pregnancy, sexual intercourse, vaginal hygiene and medications contraceptives, antibiotics and immune suppressants.

Alterations occurring in the vaginal environment may increase or decrease the selective advantages for specific microorganisms. Lactobacilli are obligate homofermenters — glucose derived from vaginal epithelial cells is used to produce lactic acid. The lactobacilli most commonly found in women of child-bearing age are Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners and Lactobacillus jensenii [ 2 ].

Healthier vaginas harbor mostly L. The majority of lactobacilli have a small genome of approximately 1. They have lost several genes that used to code specific biochemical actions. This loss has been balanced by the gain of many other significant genes. Some of these genes were acquired by the mechanism of horizontal gene transfer through bacterial conjugation, while others were acquired by phage infection.

Quite a few of these gained genes have supported protein transporter systems that have facilitated lactobacilli to attain vaginal colonization and adaptation [ 3 ]. The main role of lactobacilli is to maintain a hale and hearty balanced ecological vaginal milieu with a pH range between 3. This acidic pH is responsible for inhibiting the growth of most pathogenic bacteria.

Lactobacilli put forth this inhibition by a number of mechanisms, including the production of hydrogen peroxide, lactic acid and ribosomal-produced antimicrobial peptides bacteriocins. Lactic acid potentiates both the activity of bacteriocins and that of hydrogen peroxide [ 4 ]. The antimicrobial activity of bacteriocins includes cell membrane permeabilization with ATR amino acids and ion efflux, and transmembrane potential and pH gradient depletion.

It is worth mentioning that bacteriocins express host cell immunity and do not have hemolytic or cytotoxic activity. Lactobacilli-specific vaginotropism is facilitated by the presence of pili that act as ligands for attachment to glycolipid receptors present on vaginal epithelia cells.

Additionally, lactobacilli compete for binding to receptors on vagina epithelial cells VEC , in effect impeding pathologic microorganisms from adhering to these cells [ 5 ]. Supplementary bactericidal actions of lactobacilli products include: lactic acid, which is a potent inhibitor of Neisseria gonorrhoeae ; and hydrogen peroxide, which suppresses the growth of Gram-negative bacteria, Gram-positive facultative and obligate anaerobe bacteria, including Escherichia coli, Gardnerella vaginalis and Mobiluncus species.

Moreover, a recently identified bacteriocin, Lactocin A, specifically targets the cytoplasmic membrane of G. Furthermore, certain bacteriocins seem to be protective against an infection of HIV, while others appear to induce membrane permeabilization on Gram-negative bacteria. Lactobacillus crispatus is specifically recognized to be a hydrogen peroxide producer.

Hydrogen peroxide is involved with host myeloperoxidase and chloride ions in the formation of potent toxic oxidants that are bactericidal [ 6 ]. All of the above described actions further help lactobacilli to establish itself in the vagina and guarantee it long-term permanence to thrive with minimal competition. Vaginal immunity differs from systemic immunity. The innate immune system recognizes molecular patterns connected with pathogens pathogen-associated molecular pattern.

When a pathogen-associated molecular pattern is recognized in the vagina, it activates the systemic immune system lymphocytes T and B causing the release of proinflammatory cytokines and the start of the cellular and humoral immunity.

The innate immune system activation occurs rapidly, although several days are required for the acquired immunity to also become functional [ 1 ]. Several of these factors are active in the vagina, including soluble components such as mannose-binding lectin MBL , and complement components and membrane-associated components called as Toll-like receptors TLRs.

MBL is an antimicrobial protein synthesized by the liver and is present in the vagina. MBL binds to bacterial mannose-containing polysaccharide surfaces causing complement activation and bacteriolysis. Women deficient in MBL are more susceptible to recurrent Candida albicans infections [ 2 ].

Additionally, the vagina contains defensins — molecules with nonspecific antimicrobial activity. Moreover, in the vagina, secretory leukocyte protease inhibitor inhibits proteases, destroys Gram-positive and Gram-negative bacteria and blocks HIV has been detected.

Vaginal levels of this protein are reduced in patients with BV. Last, nitric oxide and phagocytic cells are also present in the vaginal milieu [ 1 ]. As we have seen, VECs play a very important role in vaginal immunity. A newly published manuscript regarding vaginal immunity describes the vaginal epithelium in women of child-bearing age as being comprised of loosely linked cells packed with glycogen. VECs are penetrable by bacteria and viruses in addition to molecular and cellular mediators of immune defense.

Hence, Anderson et al. TLR4 recognizes liposaccharides in Gram-negative bacteria. TLR5 responds to flagellins found in flagellated bacteria. Additionally, VECs release positively charged peptides that speedily bind to negatively charged surfaces of the pathogenic bacteria, disrupting the bacterial membrane and causing bacteriolysis [ 5 ]. VECs are likewise the first barrier against infections by C. These cells express different pattern recognition receptors by means of dectin-1, lectin like-receptor families and several of the TLRs [ 9 ].

Additionally, CARD9 contributes to signaling dectin-2 and macrophage-inducible C-type lectin, which are known to identify Candida mannans and could help to clarify the extensive range of fungal infections in women [ 12 ]. As a matter of fact, mice which are deficient in dectin-1 have a bigger predisposition to C. Dectin-1 also is responsible for signaling induction in the production of IL, IL-6 and IL via a spleen tyrosine kinase-dependent pathway [ 16 , 17 ].

In a study by Underhill et al. This hypothesis is sustained by the discovery that the site of the haplotypes encompassing the TyrX mutation was closely located to the ancient haplotype.

Second, it also suggests that the high polymorphism prevalence in these individuals could indicate a significant genetic predisposition for mucosal fungal infection. When HBD-2 is reduced, it increases the susceptibility to infection [ 1 — 2 , 5 ].

Naglik et al. Heat shock proteins HSPs are essential for life preservation. They support cell survival in varied extreme ecological conditions. They are almost pristinely evolved proteins that are present in all living creatures.

Intracellular HSP70 binds other proteins avoiding their degradation. Other researchers have confirmed that VECs inhibit C. This specifically direct antifungal activity is based on a simple epithelial cell to fungal interaction.

It is disparagingly reduced in women with Recurrent Vulvo Vaginal Candidiasis RVVC , therefore, it causes an uncontrolled development of fungi in these patients [ 21 — 24 ].

In the complicated vaginal immune milieu, antibodies producing B-lymphocytes are also locally present; they produce IgG and IgA. These antibodies are transudate from the systemic circulation and bind to pathogens provoking death by a complement-dependent mechanism or opsonization [ 8 ].

They are important speedy mechanism for fighting pathogenic microorganisms without the need for systemic immune system response.

This local complex vaginal immune system is under hormonal control, which allows vaginal protection when the adaptive immunity is downregulated by the sexual hormones essential for reproduction [ 4 ]. BV has been recognized as a chronic condition associated with a depletion of lactobacilli and a distinctive overgrowth of not only G. Among the pathogenic bacteria reported in BV are: Coriobacterium, Bacteroides, Veillonella, Ruminococcus, Streptococcus, Prevotella, Megasphera, Leptotrichia, Clostridium -like species, and a few others.

All of them support each other by their own synergistic properties [ 25 ]. Biofilm formation. Groups of lactobacilli intertwined in an extracellular matrix surrounding squamous epithelial cells. Enzymes produced by these pathogen bacteria comprise glycosidases and sialidases.

These enzymes are responsible for the characteristic low viscosity of vaginal discharge with the fishy odor of BV. The enzymatic activities of G. It is interesting to note that G. Additionally, G. At wet mount preparations, BV presents with typical clue cells. Vestraelen et al. Swidsinski et al. One of the unanswered vaginal mysteries is the absence of noticeable inflammation in patients with BV. The reasoning being that in BV fluid there is considerable overgrowth of Gram-negative and Gram-positive anaerobes; also several proinflammatory cytokines like IL-6 and IL-8 are present [ 30 , 31 ].

Since the majority of vaginal microbiota originates from the gut microbiota, the lack of inflammation could be attributed to immune tolerance acquired through evolution [ 32 — 35 ]. Other contributing factors associated with the absence of inflammation include the presence of short-chain fatty acids.

These fatty acids are the by-products of anaerobes and they modulate immune responses. They inhibit proinflammatory cytokine production and immune cell migration, and they induce several cells apoptosis including neutrophils [ 36 ]. Recently, Vitali et al. The authors correlated the clinical condition with vaginal microbiome bacterial by principal component analysis.

They concluded that L. The Center for Disease Control guidelines for bacterial vaginosis therapy are summarized in Box 1. Metronidazole, extended oral followed by vaginal maintenance therapy twice weekly for 4—6 months.

An additional important activity of lactobacillii is to produce biofilm.


Alteraciones del pH vaginal asociado a lactobacilos o bacilo de Döderlein.

Cervical bacterial colonization in women with preterm labor or premature rupture of membranes. Two cervical samples from each woman were collected and bacterioscopy and culture were performed. Association of cervical microorganisms and urinary tract infection, chorioamnionitis, fetal stress, antibiotic use, prematurity, neonatal infection, and neonatal death were evaluated. Group B streptococcus was the most prevalent organism 9. Other organisms isolated were Candida sp , Streptococcus sp , Streptococcus pneumoniae , Escherichia coli and Enterococcus sp. The most common findings of bacterioscopy were a reduced number of lactobacilli and a great number of leukocytes. Endocervical colonization was associated with a higher occurrence of urinary tract infection


Cytolytic vaginosis: misdiagnosed as candidal vaginitis.

In the last decade, there have been quite a lot of scientific advances reported regarding the immunology and pathophysiology of human vaginal microbiota. As a result, physicians have a more comprehensive understanding of the role that lactobacilli exert in the vaginal milieu and their interactions with vaginal mucosa, pathogenic bacteria and fungi. This commentary addresses those advances in vaginal microflora, vaginal epithelial cells, immunity, bacterial vaginosis BV and candidiasis. Additionally, recent reports regarding lactobacilli biofilm formation will be discussed. Last, an assessment of future implications is presented.

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