Journal of Infectious Diseases Advance Access published February 7, 2014

Role of Gadnerella vaginalis in the Pathogenesis of Bacterial Vaginosis – A Conceptual Model

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Jane R. Schwebke1, Christina A. Muzny1, William E. Josey2

1
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 USA

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2
Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA 30322

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Corresponding Author: Jane R. Schwebke, MD, University of Alabama at Birmingham, 703 19th

St South, ZRB 230, Birmingham, AL 35294-0007, 205-975-5665, 205-975-7764 (fax),

schwebke@uab.edu

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© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Abstract

Background: Bacterial vaginosis (BV) is the most common cause of vaginal discharge and is

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associated with important public health complications such as preterm birth and

acquisition/transmission of HIV and sexually transmitted infections. Continued controversy

concerning the pathogenesis of BV has led to a lack of progress in prevention and management

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of this infection.

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Methods: Development of a conceptual model for the pathogenesis of BV based on review of

past and current research.

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Results: Our model suggests that BV is initiated by the sexual transmission of Gardnerella

vaginalis (GV). GV possesses the appropriate virulence factors to adhere to host epithelium,
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create a biofilm community, and successfully compete with lactobacilli for dominance in the

vaginal environment. It is possible that the genetic diversity of GV results in virulent and

avirulent strains. Symbiotic relationships with normally dormant vaginal anaerobes lead to
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increases in the latter which contribute to the symptoms of BV.

Conclusions: GV is the pathogen responsible for the initiation of BV. Future research should
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focus on prevention of GV transmission and improved therapeutics for the biofilm infection that
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is caused by GV and host anaerobes.

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“We are prepared to present evidence that the vast majority of so-called “non-specific” bacterial

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vaginitides constitute a specific infectious entity caused by a single etiological agent… We have

assigned the name Haemophilus vaginalis to this newly isolated bacillus.” - Gardner and Dukes

1955 1.

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Overview of BV

Bacterial vaginosis (BV) is the most prevalent cause of symptomatic vaginal discharge and is

associated with complications of reproductive health including preterm birth and

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acquisition/transmission of sexually transmitted infections (STIs) including HIV2,3. Control of

BV has been advocated for decreasing the prevalence of these complications, however, the
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precise etiology of BV remains unknown. As a result, current treatment regimens and prevention

strategies are inadequate. Such a lack of understanding not only inhibits our ability to effectively
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manage women with BV but also severely impacts our ability to prevent its associated

complications. It is clear that BV is characterized by dramatic changes in the vaginal flora from a

lactobacillus - predominance to one in which there is a marked decrease in lactobacilli,

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particularly those which produce hydrogen peroxide 4. Lactobacilli are replaced by the

facultative anaerobe Gardnerella vaginalis (GV) and strictly anaerobic bacteria markedly
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increase in concentration 5. As previously reviewed 6,7, the epidemiology of BV strongly

supports that it is acquired via sexual transmission. Reviewing the literature, past and present, we
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have developed a conceptual model for the pathogenesis of BV (Figure 1).

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Conceptual Model of the Pathogenesis of BV

Development of the Vaginal Microbiome

The vaginal flora is acquired shortly after birth from maternal and environmental sources 8. In a

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study of prepubertal girls, Hill et al demonstrated the presence of anaerobic organisms in the

vaginal fluid in the majority of girls yet was unable to detect the presence of GV by culture

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despite being specifically sought 9. At puberty, with the production of estrogen, the vaginal flora

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changes to one of lactobacillus predominance. Estrogen promotes the deposition of glycogen in

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the vaginal epithelium which in turn is used as a food source by the sacchorolytic lactobacilli.

The subsequent creation of lactic acid as their metabolic end-product lowers the vaginal pH to

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<4.5 10. In addition, growth of lactobacilli increases the redox potential of the vagina thus

inhibiting the growth of the indigenous anaerobes 11.

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Acquisition of Gardnerella vaginalis

Examination of vaginal biopsy specimens demonstrates that BV is a biofilm community adherent

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to the vaginal epithelium and that GV is the predominant component of the biofilm mass 12. GV

has been recovered from vaginal fluid in close to 100% of women with clinically diagnosed BV
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. Other frequently identified BV- associated bacteria, recovered at variable rates in the vaginal

microbiome, are the genital mycoplasmas and various strict anaerobes including species of
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BVAB1, BVAB2, BVAB3, Atopobium, Leptotrichia, Megaspaera, Prevotella, and Dialister 14.

However, the assortment of strict anaerobes found in individuals with BV is heterogeneous 15.
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There have been various studies published demonstrating the detection of GV from women who

did not meet the clinical criteria for BV 16,17. These studies, however, were not rigorous in their
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definition of normal or optimal flora and failed to take into account that there are women who

neither meet the clinical definition of BV nor the definition of normal vaginal flora, i.e. women

with intermediate flora (scores of 4-6) by Nugent score 18. In a study of women with limited

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number of lifetime sex partners and lactobacillus predominant flora, we were unable to detect

GV by PCR in 60% of women who had 30 sequential daily normal Nugent scores 19. Texiera et

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al found GV in only 17.6% of “healthy” women without a clinical diagnosis of BV, however,

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there was no documentation that these women had none of the Amsel criteria nor an optimal

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Nugent score of 0-3 20. Similarly, Burton et al reported GV to be present in only 19% of women

without BV but again no Nugent score was provided in the publication 21. If GV were a part of

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the normal vaginal flora one would anticipate that it would be present in all women and present

in prepubertal girls as well 9.

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GV in the Male Genital Tract

In males, GV has been repeatedly recovered from the urethra and from seminal fluid 1,22,23. The
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presence of BV related microorganisms in the male genital tract suggests a possible reservoir and

supports the theory of sexual transmission of BV. It has been hypothesized that semen itself, due
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to its alkaline properties, may alter the acidic pH of the vagina and lead to BV 24. However,

sexual transmission of BV without exposure to semen in a heterosexual couple strongly suggests

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that it is not the semen itself which is a contributing factor to the development of BV but rather

microbes which are transmitted via sexual activity 25. By analogy, this is supported by the
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apparent sexual transmission of BV among women who have sex with women (WSW) only 26.

Eren et al were able to show that sexual partners shared the same strains of GV using

sophisticated sequence variation techniques 27. Insight into the site of colonization/infection of
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GV in the male is provided by a study of the microbiome of adolescent males. Neslon et al

found GV in 28% of urine samples but failed to detect GV from samples of the coronal sulcus 28.

In the female, BV is an infection of the squamous epithelium as opposed to the columnar

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epithelium of the cervix. Thus, it is plausible that in males, colonization/infection of the genital

tract is restricted to the distal urethra which is lined with squamous epithelium. Studies by Holst

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et al showed that BV related organisms, including GV, appeared to transiently colonize male

partners of women with BV 23. As is the case with Trichomonas vaginalis in men, another

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pathogen that infects the squamous epithelium of the vagina, it is likely that there is a high

spontaneous resolution rate due to the inhospitable environment of the distal urethra in males 29.

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Of interest, BV may be more common among WSW than in heterosexual women 30. It may be

that sexual exchange of infected vaginal fluid is a more efficient mechanism for the transmission
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of BV between WSW than behaviors that occur during heterosexual sex, thus accounting for the

higher prevalence of BV in WSW.

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Adherence of GV to Host Epithelium – Initial Steps in Invasion

The initial steps of establishing infection include adherence to host receptor sites, production of
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cytotoxic substances specific for host cells, and biofilm formation. In the case of GV, production

of vaginolysin, a cholesterol dependent cytolysin, is species-specific for human cells and encodes
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a pore-forming toxin that binds to the CD59 human complement regulatory molecule31. This

cytotoxin assists in the initial adherence of GV to the host epithelial cells 31. Investigators have
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recently examined virulence factors of GV compared to other BV associated bacteria. Patterson

et al examined adherence, biofilm formation, and cytotoxicity in vitro for GV strains which were

isolated from women with BV as well as other BV-associated bacteria including Atopobium,
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Prevotella, Mobiluncus and others. They found that among these organisms only GV

demonstrated all three virulence factors and suggested that the other organisms may be relatively

avirulent opportunists that colonize after initiation of infection by GV32. Recent work by

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Machado et al found that in-vitro, among BV-associated bacteria, GV had the greatest capacity

to adhere to epithelial cells in the presence of Lactobacillus crispatus 33.

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Virulence factors of GV

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Subsequent to initial adherence to the host cell, the invading bacteria multiply and may produce a

biofilm community as a means of future survival 34. Production of biofilm is critical to the

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survival of GV in the vagina. Sialidase, which is produced by some strains of GV, may enhance

production of biofilm through its mucinase activity 35. It has been shown in-vitro that biofilms of
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GV are far more tolerant of lactic acid and hydrogen peroxide produced by lactobacilli than are

planktonic forms of GV 36. Once this critical mass of bacteria is present, quorum sensing or

bacterial “cross-talk” occurs allowing for the bacteria to effectively manage their new
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community 37. At the same time, it is necessary for the invading pathogens to engage in

“chemical warfare” with native species. In the case of BV, the native species is composed of
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lactobacilli. It has been shown that certain species of Lactobacilli are capable of producing

inhibitory compounds, or bacteriocins, which are active against GV 38. Conversely, it has been
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shown that GV produces bacteriocins active in vitro against lactobacilli 39. GV has also been

shown to demonstrate antibiosis via other undetermined mechanisms 40. In 1991, Nagy et al
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published on their work on antibiosis, antagonistic interactions, among vaginal organisms and

concluded that “it is probable that the growth inhibition of lactobacilli caused by certain strains

of GV is one of the first steps in the change in flora characteristic of BV.”40. Evidence for
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competition between lactobacilli and GV can be demonstrated from daily vaginal Gram stains of

women with intermediate vaginal flora (Figure 2) 41. In these women, lactobacilli and GV vary

as the dominant organism throughout the menstrual cycle. GV dominates at the time of menses

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suggesting competition for iron as a substrate for the bacteria 42. It is known that heme favors the

growth of proteolytic organisms such as GV 43. It is highly likely that these observed fluctuations

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in the levels of lactobacilli and GV represent competition for resources between lactobacilli and

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GV.

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Syndrome of BV- Symbiosis in the Vaginal Microbiome

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GV, as a facultative anaerobe, may be able to tolerate the high oxidation-reduction (re-dox)

potential of a healthy vaginal microbiome, unlike strict anaerobes 11. Similar to facultative
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anaerobes involved in the initiation of oral diseases, it is likely that GV begins the process of

creating a lower re-dox potential which is then suitable for the overgrowth of strict anaerobes

normally present in very low numbers 43. Additionally, GV is a proteolytic bacterium that
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produces amino acids through its metabolism. It has been shown that Prevotella bivia, a strict

anaerobe, utilizes amino acids as its fuel source and as a result produces ammonia which in turn
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is utilized by GV 44. Therefore, a symbiotic relationship between GV and anaerobes is another

mechanism whereby GV enhances the growth of anaerobes in the vagina. Also, this symbiotic
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relationship with the production of ammonia would cause a shift to a more alkaline pH which is

inhospitable to lactobacilli 40. In-vitro work has shown that the addition of anaerobes to a GV
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biofilm enhances the growth of GV 33. These symbiotic relationships are responsible for the

microbiological findings that define BV as well as the typical symptoms of vaginal discharge

(sloughing of the vaginal epithelium visualized as “clue cells” and amine odor resulting from
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metabolic by-products of the BV-associated anaerobes 45.

Genetic Diversity in GV

Genomic sequencing has recently shown differences in virulence factors among strains of GV 46.

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Harwich et al examined virulence factors for a strain of GV from a woman with BV and one

without BV. They found impaired adherence in the non-BV isolate and suggested that there may

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be both commensal and pathogenic strains of GV 47. However, as in other studies, there is no

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mention of the Amsel or Gram stain characteristics of the woman without BV. Further, this type

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of work needs to be replicated with multiple isolates. Recent comparative genomic analyses of

17 clinical isolates of GV suggested that the species can be subdivided into 4 clades or even that

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there may be multiple species of GV. Ahmed et al found that the degree of diversity among the

strains was exceptionally high for a single species 48.

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Koch’s Postulates Fulfilled

Koch’s postulates of infection were developed in 1884 and stated that in order to prove causation
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between a microbe and a disease the following conditions must be met: 1) the microorganism

must be found in abundance in all organisms suffering from disease and not present in those
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without the disease, 2) the microorganism must be isolated from a diseased organism and grown

in pure culture, 3) the cultured microorganism should cause disease when introduced into a
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healthy organism, 4) the microorganism must be reisolated from the inoculated, diseased

experimental host and identified as being identical to the original specific causative agent. In the
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case of GV as the causative agent for BV, these postulates have been fulfilled. GV is found in

nearly 100% of cases of BV and it is isolated as the predominant bacteria from women with BV

along with small amounts of indigenous vaginal flora. Further, Criswell caused clinical BV in
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healthy women who had negative cultures for GV and no clinical signs of BV prior to vaginal

inoculation with a pure culture of GV and reisolated GV from these women after initiation of BV
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. Although GV has been isolated from women not meeting the Amsel criteria for BV this does

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not mean that these women are without disease. Further, there are many instances in which the

causative organism is present in the host but not causing overt disease.

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Summary

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BV is an important public health issue yet its pathogenesis remains controversial. The

epidemiology of BV strongly favors that it is an STI. Reviewing the available data from the past

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30 years we have developed a model for BV pathogenesis which is similar in all respects to any

human infection. There is a significant body of data supporting the pathogenicity of GV. Studies
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have confirmed that it is the dominant component of the BV biofilm, strongly suggesting that

other bacteria in the biofilm are opportunistic secondary intruders. The presence of virulence

factors in GV which were shown to be present 30 years ago has been recently confirmed by
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several studies. Prevention and treatment strategies specifically for GV should be tested to

determine their efficacy in decreasing rates of BV and its complications.

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Figure Legends

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Figure 1 As depicted in the model, GV is not part of the normal vaginal flora acquired at birth

but is transmitted through sexual activity with an infected partner. GV possesses the necessary

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virulence factors to adhere to host vaginal epithelium and successfully compete with normal

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vaginal flora for dominance. Infection with GC results in increased pH and decreased re-dox

potential favoring increased growth of host anaerobes and suppression of lactobacilli.

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Figure 2 – Day of collection with Nugent score versus lactobacillus (squares) morphotypes and

GV (triangles) morphotypes; arrows are start of menses

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Acknowledgments
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The authors would like to acknowledge Dr. Charles Rivers for his assistance with the graphics

for this manuscript.

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 Birth  of  Female   Birth  of  Male  

Acquire  endogenous  vaginal  flora  from  

mother  (lactobacilli  and  anaerobes)   Surface    and  coronal  sulcus=  
skin  associated  flora  
Urethra  =  ‘sterile’  

Addi<onal  environmental  
Puberty,  Produc<on  
acquisi<on  of  flora  
of  Estrogen  
Sex  with  exposure  to  
GV  from  infected  
Lactobacilli  predominant  vaginal   female  partner  
GV  coloniza<on  of  distal  
flora   urethra  

Sexual  exposure  
to  female  
partner  

Gardnerella  vaginalis  (GV)  adherence   Symbiosis  with  anaerobic  flora  

to  host  epithelium  
(vaginolysin  and  biofilm  forma<on)  

GV  proteolysis    and   Prevotella  bivia  

synthesis  of  
An<biosis:    GV  produc<on  of  bacteriocins     energy  u<liza<on  of  
and  other  antagonis<c  factors  to   exogenous  protein   exogenous  protein  
lactobacilli  

Lactobacilli  fail  to  maintain   NH3  

control  of  environment  and  
‘hibernate’   ↑pH,  ↓Redox   Anaerobes  

Establishment  of  BV  bacterial  community  

 

Figure 2 

3
Morphology Score (Quantity, 0‐4+)

Lactobacillus spp. morphologies

1 Gardnerella/Bacteriodes morphologies

First day of menses

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Day
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Nugent Score