Abstract
Bacterial vaginosis (BV) is the most common vaginal disorder affecting women of reproductive age and is associated with increased risk of sexually transmitted infections such as human immunodeficiency syndrome (HIV-1). Sub-Saharan Africa has the highest BV and HIV-1 burden and yet very few studies have focused on understanding the aetiology of BV and its association with HIV in this region. It has been suggested that we need to accurately diagnose and treat BV to lower the risk of HIV infection globally. However, effective diagnosis requires knowledge of what constitutes a “healthy” cervicovaginal microbiome and current studies indicate that Lactobacillus crispatus might not be the only commensal protective against BV: healthy women from different countries and ethnicities harbour alternative commensals. Microbiotas associated with BV have also shown global variation, further complicating effective diagnosis via culture-based assays as some species are difficult to grow. Antibiotics and probiotics have been suggested to be key in controlling BV infection, but the efficacy of this treatment might rely on reconstituting endogenous commensals while targeting a specific species of BV-associated bacteria (BVAB). Alternatively, therapy could inhibit essential BV bacterial growth factors e.g. sialidases or provide anti-microbial compounds e.g. lactic acid associated with a healthy cervicovaginal microbiome. But without global investigation into the mechanism of BV pathogenesis and its association with HIV, selection of such compounds could be limited to Caucasian women from certain regions. To confirm this suggestion and guide future therapy we require standardised diagnostic assays and research methodologies. This review will focus on research papers that describe the global variation of BV aetiology and how this influences the identification of determinants of BV pathogenesis and potential probiotic and antimicrobial therapy.
Similar content being viewed by others
Background
Bacterial vaginosis (BV) is associated with sexually transmitted infections (STIs) as well as pelvic inflammatory disease and pregnancy complications [1]. The most alarming association is BV’s relationship with increased risk of HIV infection [2]. The high prevalence of BV in sub-Saharan Africa (approximately 55 % of women) [3, 4] could be a very important contributing factor to the prevalence of HIV infection in this region afflicted with 60 % of global HIV infections (UNAIDS). It has thus been suggested that successful treatment of BV could ultimately lead to lowering HIV infection in this region. Unfortunately, the cause of BV remains unknown although it is generally characterised by the outgrowth of “unhealthy” facultative and obligate anaerobic bacteria with a concomitant decrease in the levels of “healthy” Lactobacillus spp. within the genital tract [5]. Given the polymicrobial nature of BV and recent evidence, it is highly likely that pathogenesis of BV-associated bacteria (BVAB) is shaped not only by the bacterial populations present in the genital tract but also by specific host factors. Human genetic host immunity and the identity of “healthy” and “unhealthy” genital tract bacteria differ globally, suggesting that diagnosis and treatment of BV might need to be adjusted according to region. This approach to therapy is unrealistic in resource-poor settings and before we accept this strategy as gold standard we need to confirm our current understanding of “healthy” vaginal microflora and the identity of BVAB. This review aims to highlight the need for studies in sub-Saharan Africa to investigate the aetiology of BV in this region using standardised protocols. Furthermore, understanding the mechanism by which BV increases the risk of HIV will provide new targets for antimicrobial agents.
What constitutes a healthy cervicovaginal tract microbiome?
Seventy percent of healthy Caucasian females carry predominantly genital Lactobacilli spp. [6] with the most common being L. crispatus, L. gasseri, L. jensenii and L. iners [7]. Meta-analysis of a number of studies indicated that L. crispatus was significantly associated with the absence of BV, and transition to BVAB occurred via outgrowth of L. iners, confirming a previous study that L. gasseri and/or L. iners are associated with BV-related microflora whereas L. crispatus protected against dysbiosis [8, 9]. However, studies focused on sub-Saharan countries have indicated that the predominant Lactobacillus species varied both within and between countries. Three South African studies reported conflicting results: one indicated that L. crispatus was associated with normal cervicovaginal microflora (p = 0.024), supporting studies on Caucasian women, whereas another showed that BV- and HIV-negative women carried predominantly L. salivarius. Finally, the last study showed that most women carried both L. crispatus and L. jensenii and that L. jensenii and not L. crispatus was associated with lack of BV (p = 0.053) [10–12]. The majority of women from Kenya, Rwanda, South Africa and Tanzania had predominantly genital L. iners with coincident anaerobic microbes [13]. Another descriptive cross-sectional study observed no difference between South African and Kenyan women with L. crispatus and L. vaginalis associated with low Nugent scores [14]. Nigerian women were mostly colonized with genital L. iners and L. gasseri and Ugandan women carried primarily L. reuteri, L. crispatus, L. vaginalis and L. jensenii [15, 16]. Therefore, although Lactobacilli were found in women from different countries, the dominant species differed and some healthy women carried non-Lactobacilli anaerobic microflora.
These results were confirmed when women from different ethnicities were compared from the same region. It is unknown why black women have a higher prevalence of BV than Caucasians [17, 18]. However, a contributing factor could be that the cervicovaginal microflora of healthy women differs according to race [19]. Srinivasan et al. indicated that 28 taxa were differentially associated with race in the USA (p < 0.05) with Leptotrichia amnionii, Atopobium vaginae and BVAB1 found in more African-American BV-negative women than Caucasians. Furthermore, the healthy microbiomes of African-American—women were dominated by L. iners and those of Caucasians, L. crispatus [20]. Healthy microbiomes also varied among Hispanic, African-American, white and Asian women where the cervicovaginal tracts of white and Asian women were dominated by Lactobacilli spp. and African-American and Hispanic individuals carried more non-Lactobacilli anaerobic bacteria (p < 0.0001) [21]. Interestingly, a study of black South African women also reported that most asymptomatic women carried non-Lactobacillus species, similar to African-American women. The dominant Lactobacillus spp. was also L. iners, suggesting that healthy women of African descent could be less likely to carry cervicovaginal L. crispatus [8]. As L. iners could play a role in BV pathology, this finding could in part explain the high incidence of BV amongst black women especially in Southern Africa [22]. However, Kenyon et al. cautioned against this suggestion given that the prevalence of BV in some African countries such as Burkina Faso is quite low [23].
BV diagnosis is usually based on four physiological Amsel criteria or Nugent score—a gram stain that determines the relative amounts of gram-positive Lactobacilli and gram-negative rods (low score of 0–3 indicating mainly Lactobacilli/normal vaginal “flora”; high score of 8–10 indicating BV). Recently, BV-associated dysbiosis was shown not to correlate with three of the four Amsel criteria and the Amsel method was unlikely to identify BV-positive women if they lacked dominant Lactobacilli species [13]. This is not reassuring as diagnosis of BV based on Amsel criteria (malodour, discharge, high pH and clue cells) is most commonly used in developing countries.
How could Lactobacilli protect against BV and HIV?
Variation in healthy genital tract Lactobacilli commensals across countries and ethnicities could lead to varying levels of protection against BV and HIV-1. Comparative functional genomic studies have shown that Lactobacillus spp. have evolved in a species-specific manner to adjust to the cervicovaginal environment, each expressing alternative adaptive factors. Therefore, microbes could influence the health of the genital tract through multiple mechanisms [24] such as the production of bacteriocins, lowering of the genital tract pH, and/or release of hydrogen peroxide [25–27]. Lactobacilli produce strain-specific bacteriocins such as reuterin by L. reuteri and lactocepin by L. casei and L. paracase [28]. Despite being the focus of many earlier studies, it is unlikely that hydrogen peroxide plays a role in HIV acquisition as the level of hydrogen peroxide produced by Lactobacilli in the hypoxic environment of the genital tract would be too low to inhibit HIV [29].
Overall, high pH correlated best with high Nugent scores [21] and low pH prevented HIV infection [30]. However, it was shown that lactic acid and not pH was responsible for inhibiting HIV-1 and BVAB [29, 31]. Cervicovaginal microbiome pyrosequencing showed predominance of lactic acid anaerobes in black and Hispanic women, suggesting that the presence of lactic acid could play a very important role in defining healthy vaginas and not a specific bacterial species [21]. Furthermore, the presence of any Lactobacillus spp. was associated with lower risk of HIV infection [3] and lower levels of HIV RNA in cervical vaginal lavages (CVLs) [32]. However, another study showed that the level of protection could be strain-specific: L. crispatus was better associated with lower HIV RNA levels than L. iners [33]. These species rarely co-dominate, probably due to competition and the relative ability of each species to adapt to different environments [24].
Witkin et al. [35] reported that Lactobacillus spp. produced either l- or d-lactic acid and only the l-isoform inhibited HIV-1 infection. l-lactic acid induces the IL-23/IL-17 T cell pathway, release of pro-inflammatory cytokines, lymphocyte activation and increase in metalloproteases responsible for disruption of the cervix. The release of different cytokines depended on the species of Lactobacillus present [34] and could be due to genetic differences between species as L. crispatus, L. gasseri and L. iners do not have the same number of copies of the l- and d-lactate dehydrogenase (LDH) genes [35]. Therefore, protection might be Lactobacillus spp. dependent and as the commensals of healthy women differ globally, it is likely that microbes other than Lactobacilli could be protective via similar mechanisms (production of l-lactic acid) or novel ways, altering the definition of a “healthy” genital tract.
Could a specific anaerobe predict BV and HIV?
A number of studies have identified different bacteria associated with BV in Caucasian women such as Veillonella parvula, Bacteroides, Peptococcus asaccharolyticus, Gardnerella vaginalis, Mobiluncus spp., Mycoplasma hominis and Chlamydia trachomatis [36–38]. Unravelling the BV microbiome using molecular techniques has helped to identify non-culturable bacteria such as Atopobium vaginae, newly identified BVAB strains (BVAB1-3), Megasphaera spp. and Leptotrichia spp. [21]. However, as these bacteria are also lactic acid producers and found in BV-asymptomatic women, it has been suggested that they do not indicate unhealthy vaginas. In sub-Saharan Africa, BV was associated with G. vaginalis in Kenya but not in Uganda [39] and Prevotella bivia or Lachnospiraceae were identified in Tanzania [40]. Mycoplasma hominis infected 35 % of HIV-negative Nigerian women whereas G. vaginalis, Prevotella spp., Mobiluncus, Atopobium spp. and E. coli, which predominate in Caucasians, were not identified [15]. Mycoplasma lacks a cell wall and thus cannot be identified using the Nugent scoring system. It is thus possible that this organism is underrepresented in Caucasian BV populations because of the type of diagnostic assay used in some studies [32, 41]. The presence of both G. vaginalis and M. hominis in the genital tract was associated with increased CVL HIV RNA. When analysis compared these two organisms singly only Mycoplasma remained significantly associated with HIV levels (p = 0.0001) [32]. This could suggest that Mycoplasma plays an important role in HIV acquisition and that correct screening and diagnostic assays should be used to confirm whether it is associated with BV and HIV globally.
The primary bacteria associated with BV biofilms are G. vaginalis and A. vaginae [42, 43]. It has been suggested that the genital epithelium is colonised by G. vaginalis first and its biofilm production facilitates the colonisation of secondary anaerobes [44–46]. However, as G. vaginalis has been isolated from healthy women and introduction of vaginal secretions and not inoculation with pure G. vaginalis culture resulted in BV, it was thought to be a component of the normal genital microbiome and thus not the causative agent for BV [47–50]. Machado et al. [45] showed that G. vaginalis adherence displaced L. crispatus, grew threefold better in the presence of certain anaerobes and encouraged the biofilm growth of mainly P. bivia. The authors suggest an interdependent relationship between Lactobacilli and BVAB and that this association might be species-specific [46].
Schwebke et al. [20] reviewed convincing evidence as to the role of G. vaginalis in BV as nearly 100 % of women with BV carry this specific bacterium whereas other colonising anaerobes are highly heterogeneous. They also suggest that G. vaginalis diversity could result in both pathogenic and non-pathogenic strains [45] with only specific biofilm-causing strains responsible for BV [51]. Genomic sequencing and in vitro analysis of two G. vaginalis strains- one from a BV-infected woman and the other from a BV-negative women- showed that the former strain was pathogenic with enhanced biofilm production [52]. In support of this theory, Vaginolysin cytotoxicity also varied between G. vaginalis strains, reiterating the importance of genetic variation between strains. What this means for BV in sub-Saharan Africa where BV microbiomes differ between countries remains unknown.
How could BV anaerobes enhance HIV infection?
A heat stable factor found in CVLs of BV-infected women enhanced HIV replication, suggesting that BVAB could increase HIV acquisition directly [53–55]. Vaginolysin produced by G. vaginalis facilitates bacterial growth [56] and enhances HIV infection by permeabilising the cervicovaginal epithelium [52].
HIV-1 Envelope (Env) glycosylation may play a role in HIV transmission and thus glycosidases that alter viral glycans could help select specific transmitted founder variants. Dendritic cell DC-SIGN receptor binds to HIV via Env glycans and enables trans-infection of CD4+ T cells, thus facilitating HIV transmission [57]. One study showed that CVLs from BV-infected women had higher levels of sialidase, α-galactosidase, β-galactosidase and α-glucosidase than uninfected women, suggesting that BVAB produce enzymes that have the potential to alter the glycome of the genital tract [58]. Using lectin microarray profiling of CVLs of women with and without BV indicated that the number of high mannose N-glycans decreased in the presence of BV [59]. The authors suggest that the high mannose residues on the glycoproteins of the genital mucosa outcompete HIV Env for binding to DC-SIGN or macrophage mannose receptor, preventing infection of macrophages and dendritic cells involved in HIV transmission [60–62].
Bacterial vaginosis was also associated with fewer CVL sialic acid residues as expected with an increase in sialidase levels associated with the onset of BV [63]. Sialidase levels are currently used to diagnose BV using the BVBlue system [64]. Sialidase secreted by Bacteroides spp. and G. vaginalis help produce biofilms and both mucinases and sialidases are involved in STIs (reviewed by Wiggins) [65] by disrupting the integrity of the mucosa, facilitating the adhesion of pathogens to mucins and/or underlying epithelial cells [66]. The negatively charged sialic acid molecules at the terminal ends of the O-linked sugar chains determine changes in mucosal viscosity [67] influencing viral access to epithelial cells. Sialidases could also directly affect HIV infection as both gp120 and CD4 carry terminal sialic acid residues. In fact, treatment of cells or HIV with sialidase enhanced HIV infection [68–70], suggesting that removal of sialic acids could facilitate virus-target cell binding and thus enhance transmission. Future studies should investigate the significance of this finding on the transmission of HIV by evaluating the effect of sub-Saharan-specific BVAB on CVL sialidase levels of BV-positive women and their impact on HIV replication.
Could the immune response to BV facilitate HIV transmission?
It has been suggested that the genital tract immune response plays a very important role in the pathophysiological condition of BV [71] because interactions between genital epithelial cells and microbiota regulate the innate immune response. Therefore, disruption of the delicate balance between microbial species could alter pathogen susceptiblity, facilitating HIV replication/shedding in the genital tract and [72] ultimately leading to increased female to male HIV transmission [73, 74]. Schellenberg et al. [75] reviewed studies that indicated that BV-associated inflammation occured via activation of Toll-like receptors (TLRs). Royse et al. [76] indicated that a genetic variation in TLR4, TLR9 and TLR2 of African-American adolescents was associated with recurrence of BV in HIV-infected individuals. A polymorphism in TLR2 was also associated with BV and these authors suggest that specific bacteria could have differential effects on TLRs [77]. Mitchell et al. [34] reviewed findings that showed that different BVAB were associated with varying cytokines and activation of the innate immunity of fully differentiated vaginal epithelial cell aggregates was species-specific: A. vaginae increased epithelial cell mucins and pro-inflammatory cytokines; L. iners activated pattern-recognition receptor-signaling activity [77] whereas Prevotella bivia and L. crispatus seemed to have no effect. Therefore infection with A. vaginae could induce a pro-inflammatory immune response that disrupts barrier functions whereas other microbes could elicit different responses [78]. This reiterates the need to fully understand genital immunity associated with BV in sub-Saharan Africa, noting the difference in global BV-associated microbiomes discovered thus far.
Could probiotics and antibiotics treat BV and lower risk of HIV infection?
Treatment of BV with metronidazole did not prevent recurrent BV infections nor lower levels of viral RNA (shed virus) and viral DNA (cell associated) in CVLs [79]. One reason for this is that the biofilm barrier needs to be overcome before anti-microbial agents can gain access to the adherent bacteria. Retrocyclin not only inhibits Vaginolysin and thus prevents biofilm production, it also has anti-HIV activity and is currently being evaluated as an anti-HIV microbicide [80]. To prevent microbicides from altering the genital innate immune response, disrupting the integrity of the mucosal epithelium and enhancing HIV acquisition [81, 82], innate immune regulators and/or antimicrobial agents that eliminate BV-associated microbiota without disrupting beneficial Lactobacilli spp. should be included [83]. One potential candidate, carbohydrate binding agents (CBAs) has been shown to prevent CD4 T cell HIV infection, cell–cell fusion, binding to DC-SIGN and trans-infection of CD4 T cells without affecting the growth of commensal Lactobacilli [84].
Metronidazole and clindamycin do not prevent recurrent BV infections as the Lactobacilli population is rarely reconstituted [85]. Probiotics could thus be highly beneficial- modulating the mucosal flora, maintaining the integrity of the epithelial barrier and regulating the immune response. Hydrogen peroxide-producing Lactobacilli have been shown to be protective against a number of bacterial infections and have been used in probiotics [86, 87]. Live Lactobacilli and the culture supernatant of Lactobacilli inhibited HIV infection. The most effective of the Lactobacilli tested was L. gasseri [88]. As dysbiosis results in inflammation [89], selection of probiotics that do not disturb the natural flora and thus the innate immune response is very important. Numerous studies have tested different Lactobacillus strains with varying effects [6]. Homayouni et al. [90] review on probiotic trials between 1990 and 2011 suggested that combination treatment with L. acidophilus, L. rhamnosus, and L. fermentum normalised cervicovaginal microbiome resulting in curing BV and preventing relapse. In contrast, L. fermentum and L. plantarum were shown by Vicariotto et al. [91] to reduce biofilms in vitro and cure BV in human trials whereas L. crispatus, L. reuteri, and L. iners, disrupted biofilms in another study [92].
Despite this evidence, review and analysis of a number of studies in 2009 indicated that there was insufficient evidence to support the use of probiotics in the treatment of BV and that large randomised trials with standard methodology was still outstanding [93]. Factors that need to be considered are the application of unsuitable bacterial strains and/or colonisation difficulties in the presence of BVAB [86, 94–96]. A randomized double blind study in 2009 indicated that the L. crispatus probiotic was able to colonise only in the absence of endogenous L. crispatus, lack of condom use and without recent sexual activity, suggesting that the choice of Lactobacillus probiotic, the identity of the natural microflora and sexual practices could affect the efficacy of probiotics [96]. Due to the high variability of the genital microbiome in the genital tract of women [35], it is most likely that a single probiotic strain might not be sufficient to prevent BV or HIV infection.
Conclusion
Studies suggest that BV pathology is highly dependent on Lactobacilli spp., BVAB and host genetic differences within the context of social behaviour. This synergy is complicated by differences in Lactobacilli spp. and BVAB across race and nationality so that diagnosis and treatment within resource-poor settings such as sub-Saharan Africa requires new consideration. We need to know whether differences across regions and ethnicities reflect true diversity or are due to study design. Thus we need to first standardise a global methodology for BV screening and identification of commensals and BVAB before rigorous longitudinal comparisons between different races and countries are carried out. In conjunction with this, basic research needs to apply in vitro assays that circumvent CVL donor variation to identify novel markers of BV and potential targets for drug design. Without a global approach, controlling BV in sub-Saharan Africa is highly unlikely.
References
Schwebke JR. New concepts in the etiology of bacterial vaginosis. Curr Infect Dis Rep. 2009;11(2):143–7.
Cohen CR, Lingappa JR, Baeten JM, Ngayo MO, Spiegel CA, Hong T, et al. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med. 2012;9:6.
Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL, Chohan B, et al. Vaginal Lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180(6):1863–8.
Bukusi EA, Cohen CR, Meier AS, Waiyaki PG, Nguti R, Njeri JN, et al. Bacterial vaginosis: risk factors among Kenyan women and their male partners. Sex Transm Dis. 2006;33(6):361–7.
Lamont RF, Sobel JD, Akins RA, Hassan SS, Chaiworapongsa T, Kusanovic JP, et al. The vaginal microbiome: new information about genital tract flora using molecular based techniques. BJOG. 2011;118(5):533–49.
Petrova MI, Lievens E, Malik S, Imholz N, Lebeer S. Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Front Physiol. 2015;6:81.
Antonio MA, Hawes SE, Hillier SL. The identification of vaginal Lactobacillus species and the demographic and microbiologic characteristics of women colonized by these species. J Infect Dis. 1999;180(6):1950–6.
van de Wijgert JH, Borgdorff H, Verhelst R, Crucitti T, Francis S, Verstraelen H, et al. The vaginal microbiota: what have we learned after a decade of molecular characterization? PLoS One. 2014;9:8.
Verstraelen H, Verhelst R, Claeys G, De Backer E, Temmerman M, Vaneechoutte M. Longitudinal analysis of the vaginal microflora in pregnancy suggests that L. crispatus promotes the stability of the normal vaginal microflora and that L. gasseri and/or L. iners are more conducive to the occurrence of abnormal vaginal microflora. BMC Microbiol. 2009;9:116.
Pendharkar S, Magopane T, Larsson PG, de Bruyn G, Gray GE, Hammarstrom L, et al. Identification and characterisation of vaginal Lactobacilli from South African women. BMC Infect Dis. 2013;13:43.
Dols JA, Reid G, Kort R, Schuren FH, Tempelman H, Bontekoe TR, et al. PCR-based identification of eight Lactobacillus species and 18 hr-HPV genotypes in fixed cervical samples of South African women at risk of HIV and BV. Diagn Cytopathol. 2012;40(6):472–7.
Damelin LH, Paximadis M, Mavri-Damelin D, Birkhead M, Lewis DA, Tiemessen CT. Identification of predominant culturable vaginal Lactobacillus species and associated bacteriophages from women with and without vaginal discharge syndrome in South Africa. J Med Microbiol. 2011;60(2):180–3.
Gautam R, Borgdorff H, Jespers V, Francis SC, Verhelst R, Mwaura M, et al. Correlates of the molecular vaginal microbiota composition of African women. BMC Infect Dis. 2015;15:86.
Jespers V, van de Wijgert J, Cools P, Verhelst R, Verstraelen H, Delany-Moretlwe S, et al. The significance of Lactobacillus crispatus and L. vaginalis for vaginal health and the negative effect of recent sex: a cross-sectional descriptive study across groups of African women. BMC Infect Dis. 2015;15:115.
Anukam KC, Reid G. Organisms associated with bacterial vaginosis in Nigerian women as determined by PCR-DGGE and 16S rRNA gene sequence. Afr Health Sci. 2007;7(2):68–72.
Jin L, Tao L, Pavlova SI, So JS, Kiwanuka N, Namukwaya Z, et al. Species diversity and relative abundance of vaginal lactic acid bacteria from women in Uganda and Korea. J Appl Microbiol. 2007;102(4):1107–15.
Peipert JF, Lapane KL, Allsworth JE, Redding CA, Blume JD, Stein MD. Bacterial vaginosis, race, and sexually transmitted infections: does race modify the association? Sex Transm Dis. 2008;35(4):363–7.
Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001–2004 National health and nutrition examination survey data. Obstet Gynecol. 2007;109(1):114–20.
Zhou X, Brown CJ, Abdo Z, Davis CC, Hansmann MA, Joyce P, et al. Differences in the composition of vaginal microbial communities found in healthy Caucasian and black women. ISME J. 2007;1(2):121–33.
Srinivasan S, Hoffman NG, Morgan MT, Matsen FA, Fiedler TL, Hall RW, et al. Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria. PLoS One. 2012;7:6.
Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 2011;108(Suppl 1):4680–7.
Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42(5):965–76.
Kenyon C, Colebunders R, Crucitti T. The global epidemiology of bacterial vaginosis: a systematic review. Am J of Obstet Gynecol. 2013. doi:10.1016/j.ajog.2013.05.006.
Mendes-Soares H, Suzuki H, Hickey RJ, Forney LJ. Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal Lactobacilli to their environment. J Bacteriol. 2014;196(7):1458–70.
Branco KM, Nardi RM, Moreira JL, Nunes AC, Farias LM, Nicoli JR, et al. Identification and in vitro production of Lactobacillus antagonists from women with or without bacterial vaginosis. Braz J Med Biol Res. 2010;43(4):338–44.
Matu MN, Orinda GO, Njagi EN, Cohen CR, Bukusi EA. In vitro inhibitory activity of human vaginal Lactobacilli against pathogenic bacteria associated with bacterial vaginosis in Kenyan women. Anaerobe. 2010;16(3):210–5.
Klebanoff SJ, Coombs RW. Viricidal effect of Lactobacillus acidophilus on human immunodeficiency virus type 1: possible role in heterosexual transmission. J Exp Med. 1991;174(1):289–92.
Cicenia A, Scirocco A, Carabotti M, Pallotta L, Marignani M, Severi C. Postbiotic activities of Lactobacilli-derived factors. J Clin Gastroenterol. 2014;48(Suppl 1):18–22.
O’Hanlon DE, Moench TR, Cone RA. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis. 2011;11:200.
Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-Hanssen P, et al. Hydrogen peroxide-producing Lactobacilli and acquisition of vaginal infections. J Infect Dis. 1996;174(5):1058–63.
Aldunate M, Tyssen D, Johnson A, Zakir T, Sonza S, Moench T, et al. Vaginal concentrations of lactic acid potently inactivate HIV. J Antimicrob Chemother. 2013;68(9):2015–25.
Sha BE, Zariffard MR, Wang QJ, Chen HY, Bremer J, Cohen MH, et al. Female genital-tract HIV load correlates inversely with Lactobacillus species but positively with bacterial vaginosis and Mycoplasma hominis. J Infect Dis. 2005;191(1):25–32.
Borgdorff H, Tsivtsivadze E, Verhelst R, Marzorati M, Jurriaans S, Ndayisaba GF, et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J. 2014;8(9):1781–93.
Mitchell C, Marrazzo J. Bacterial vaginosis and the cervicovaginal immune response. Am J Reprod Immunol. 2014;71(6):555–63.
Witkin SS, Mendes-Soares H, Linhares IM, Jayaram A, Ledger WJ, Forney LJ. Influence of vaginal bacteria and d- and l-lactic acid isomers on vaginal extracellular matrix metalloproteinase inducer: implications for protection against upper genital tract infections. M Bio. 2013;4:4.
Piot P, Van Dyck E, Godts P, Vanderheyden J. The vaginal microbial flora in non-specific vaginitis. Eur J Clin Microbiol. 1982;1(5):301–6.
Holst E, Wathne B, Hovelius B, Mardh PA. Bacterial vaginosis: microbiological and clinical findings. Eur J Clin Microbiol. 1987;6(5):536–41.
McGregor JA, French JI, Jones W, Milligan K, McKinney PJ, Patterson E, et al. Bacterial vaginosis is associated with prematurity and vaginal fluid mucinase and sialidase: results of a controlled trial of topical clindamycin cream. Am J Obstet Gynecol. 1994;170(4):1048–59.
Nzomo J, Waiyaki P, Waihenya R. Bacterial vaginosis and correlates in women of reproductive age in Thika, Kenya. Adv Microbiol. 2013;3:249–54.
Hummelen R, Fernandes AD, Macklaim JM, Dickson RJ, Changalucha J, Gloor GB, et al. Deep sequencing of the vaginal microbiota of women with HIV. PLoS One. 2010;5:8.
Sha BE, Chen HY, Wang QJ, Zariffard MR, Cohen MH, Spear GT. Utility of Amsel criteria, Nugent score, and quantitative PCR for Gardnerella vaginalis, Mycoplasma hominis, and Lactobacillus spp. for diagnosis of bacterial vaginosis in human immunodeficiency virus-infected women. J Clin Microbiol. 2005;43(9):4607–12.
Swidsinski A, Mendling W, Loening-Baucke V, Ladhoff A, Swidsinski S, Hale LP, et al. Adherent biofilms in bacterial vaginosis. Obstet Gynecol. 2005;106(5):1013–23.
Swidsinski. An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with oral metronidazole. Am J Obstet Gynecol. 2008;198:1.
Alves P, Castro J, Sousa C, Cereija TB, Cerca N. Gardnerella vaginalis outcompetes 29 other bacterial species isolated from patients with bacterial vaginosis, using in an in vitro biofilm formation model. J Infect Dis. 2014;210(4):593–6.
Schwebke JR, Muzny CA, Josey WE. Role of Gardnerella vaginalis in the pathogenesis of bacterial vaginosis: a conceptual model. J Infect Dis. 2014;210(3):338–43.
Machado A, Jefferson KK, Cerca N. Interactions between Lactobacillus crispatus and bacterial vaginosis (BV)-associated bacterial species in initial attachment and biofilm formation. Int J Mol Sci. 2013;14(6):12004–12.
Hyman RW, Fukushima M, Diamond L, Kumm J, Giudice LC, Davis RW. Microbes on the human vaginal epithelium. Proc Natl Acad Sci USA. 2005;102(22):7952–7.
Spiegel CA, Davick P, Totten PA, Chen KC, Eschenbach DA, Amsel R, et al. Gardnerella vaginalis and anaerobic bacteria in the etiology of bacterial (nonspecific) vaginosis. Scand J Infect Dis Suppl. 1983;40:41–6.
Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis: a newly defined specific infection previously classified non-specific vaginitis. Am J Obstet Gynecol. 1955;69(5):962–76.
Totten PA, Amsel R, Hale J, Piot P, Holmes KK. Selective differential human blood bilayer media for isolation of Gardnerella (Haemophilus) vaginalis. J Clin Microbiol. 1982;15(1):141–7.
Verstraelen H, Swidsinski A. The biofilm in bacterial vaginosis: implications for epidemiology, diagnosis and treatment. Curr Opin Infect Dis. 2013;26(1):86–9.
Harwich MD Jr, Alves JM, Buck GA, Strauss JF 3rd, Patterson JL, Oki AT, et al. Drawing the line between commensal and pathogenic Gardnerella vaginalis through genome analysis and virulence studies. BMC Genom. 2010;11:375.
Spear GT, Al-Harthi L, Sha B, Saarloos MN, Hayden M, Massad LS, Benson C, Roebuck KA, Glick NR, Landay A. A potent activator of HIV-1 replication is present in the genital tract of a subset of HIV-1-infected and uninfected women. AIDS. 1997;11(11):1319–26.
Olinger GG, Hashemi FB, Sha BE, Spear GT. Association of indicators of bacterial vaginosis with a female genital tract factor that induces expression of HIV-1. AIDS. 1999;13(14):1905–12.
Cohn JA, Hashemi FB, Camarca M, Kong F, Xu J, Beckner SK, et al. HIV-inducing factor in cervicovaginal secretions is associated with bacterial vaginosis in HIV-1-infected women. J Acquir Immune Defic Syndr. 2005;39(3):340–6.
Gelber SE, Aguilar JL, Lewis KL, Ratner AJ. Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis. J Bacteriol. 2008;190(11):3896–903.
Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000;100(5):587–97.
Moncla BJ, Chappell CA, Mahal LK, Debo BM, Meyn LA, Hillier SL. Impact of bacterial vaginosis, as assessed by nugent criteria and hormonal status on glycosidases and lectin binding in cervicovaginal lavage samples. PLoS One. 2015;10:5.
Wang L, Koppolu S, Chappell C, Moncla BJ, Hillier SL, Mahal LK. Studying the effects of reproductive hormones and bacterial vaginosis on the glycome of lavage samples from the cervicovaginal cavity. PLoS One. 2015;10:5.
Fanibunda SE, Modi DN, Gokral JS, Bandivdekar AH. HIV gp120 binds to mannose receptor on vaginal epithelial cells and induces production of matrix metalloproteinases. PLoS One. 2011;6:11.
Harman AN, Kim M, Nasr N, Sandgren KJ, Cameron PU. Tissue dendritic cells as portals for HIV entry. Rev Med Virol. 2013;23(5):319–33.
Jadhav SK, Velhal SM, Deshpande A, Bandivdekar AH. Association of human mannose receptor in sexual transmission of human immunodeficiency virus in serodiscordant couples. AIDS Res Hum Retroviruses. 2013;29(1):156–63.
Briselden AM, Moncla BJ, Stevens CE, Hillier SL. Sialidases (neuraminidases) in bacterial vaginosis and bacterial vaginosis-associated microflora. J Clin Microbiol. 1992;30(3):663–6.
Myziuk L, Romanowski B, Johnson SC. BVBlue test for diagnosis of bacterial vaginosis. J Clin Microbiol. 2003;41(5):1925–8.
Wiggins R, Hicks SJ, Soothill PW, Millar MR, Corfield AP. Mucinases and sialidases: their role in the pathogenesis of sexually transmitted infections in the female genital tract. Sex Transm Infect. 2001;77(6):402–8.
Lewis AL, Lewis WG. Host sialoglycans and bacterial sialidases: a mucosal perspective. Cell Microbiol. 2012;14(8):1174–82.
Scudder PR, Chantler EN. Control of human cervical mucin glycosylation by endogenous fucosyl and sialyltransferases. Adv Exp Med Biol. 1982;144:265–7.
Stamatos NM, Gomatos PJ, Cox J, Fowler A, Dow N, Wohlhieter JA, et al. Desialylation of peripheral blood mononuclear cells promotes growth of HIV-1. Virology. 1997;228(2):123–31.
Stamatos NM, Curreli S, Zella D, Cross AS. Desialylation of glycoconjugates on the surface of monocytes activates the extracellular signal-related kinases ERK 1/2 and results in enhanced production of specific cytokines. J Leukoc Biol. 2004;75(2):307–13.
Hu H, Shioda T, Moriya C, Xin X, Hasan MK, Miyake K, et al. Infectivities of human and other primate lentiviruses are activated by desialylation of the virion surface. J Virol. 1996;70(11):7462–70.
Cauci S, Scrimin F, Driussi S, Ceccone S, Monte R, Fant L, et al. Specific immune response against Gardnerella vaginalis hemolysin in patients with bacterial vaginosis. Am J Obstet Gynecol. 1996;175(6):1601–5.
Fichorova RN, Yamamoto HS, Delaney ML, Onderdonk AB, Doncel GF. Novel vaginal microflora colonization model providing new insight into microbicide mechanism of action. M Bio. 2011;2:6.
Mitchell C, Balkus JE, Fredricks D, Liu C, McKernan-Mullin J, Frenkel LM, et al. Interaction between Lactobacilli, bacterial vaginosis-associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women. AIDS Res Hum Retroviruses. 2013;29(1):13–9.
Baeten JM, Kahle E, Lingappa JR, Coombs RW, Delany-Moretlwe S, Nakku-Joloba E, et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci Transl Med. 2011;3:77.
Schellenberg JJ, Plummer FA. The microbiological context of HIV resistance: vaginal microbiota and mucosal inflammation at the viral point of entry. Int J Inflam. 2012. doi:10.1155/2012/131243.
Royse KE, Kempf MC, McGwin G Jr, Wilson CM, Tang J, Shrestha S. Toll-like receptor gene variants associated with bacterial vaginosis among HIV-1 infected adolescents. J Reprod Immunol. 2012;96(1–2):84–9.
Taylor BD, Darville T, Ferrell RE, Ness RB, Kelsey SF, Haggerty CL. Cross-sectional analysis of toll-like receptor variants and bacterial vaginosis in African-American women with pelvic inflammatory disease. Sex Transm Infect. 2014;90(7):563–6.
Doerflinger SY, Throop AL, Herbst-Kralovetz MM. Bacteria in the vaginal microbiome alter the innate immune response and barrier properties of the human vaginal epithelia in a species-specific manner. J Infect Dis. 2014;209(12):1989–99.
Wang CC, McClelland RS, Reilly M, Overbaugh J, Emery SR, Mandaliya K, et al. The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1. J Infect Dis. 2001;183(7):1017–22.
Sassi AB, Bunge KE, Hood BL, Conrads TP, Cole AM, Gupta P, et al. Preformulation and stability in biological fluids of the retrocyclin RC-101, a potential anti-HIV topical microbicide. AIDS Res Ther. 2011;8:27.
Trifonova RT, Doncel GF, Fichorova RN. Polyanionic microbicides modify Toll-like receptor-mediated cervicovaginal immune responses. Antimicrob Agents Chemother. 2009;53(4):1490–500.
Hladik F, Doncel GF. Preventing mucosal HIV transmission with topical microbicides: challenges and opportunities. Antiviral Res. 2010;88(Suppl 1):3–9.
Gordts SC, Ferir G, D’Huys T, Petrova MI, Lebeer S, Snoeck R, et al. The low-cost compound lignosulfonic acid (LA) exhibits broad-spectrum anti-HIV and anti-HSV activity and has potential for microbicidal applications. PLoS One. 2015;10:7.
Petrova MI, Mathys L, Lebeer S, Noppen S, Van Damme EJ, Tanaka H, et al. Inhibition of infection and transmission of HIV-1 and lack of significant impact on the vaginal commensal Lactobacilli by carbohydrate-binding agents. J Antimicrob Chemother. 2013;68(9):2026–37.
Bradshaw CS, Morton AN, Hocking J, Garland SM, Morris MB, Moss LM, et al. High recurrence rates of bacterial vaginosis over the course of 12 months after oral metronidazole therapy and factors associated with recurrence. J Infect Dis. 2006;193(11):1478–86.
Falagas M, Betsi GI, Athanasiou S. Probiotics for the treatment of women with bacterial vaginosis. Clin Microbiol Infect. 2007;13(7):657–64.
Rolfe RD. The role of probiotic cultures in the control of gastrointestinal health. J Nutr. 2000;130(Suppl 2):396–402.
Zabihollahi R, Motevaseli E, Sadat SM, Azizi-Saraji AR, Asaadi-Dalaie S, Modarressi MH. Inhibition of HIV and HSV infection by vaginal Lactobacilli in vitro and in vivo. Daru. 2012;20(1):53.
Licciardi PV, Tang ML. Vaccine adjuvant properties of probiotic bacteria. Discov Med. 2011;12(67):525–33.
Homayouni A, Bastani P, Ziyadi S, Mohammad-Alizadeh-Charandabi S, Ghalibaf M, Mortazavian AM, et al. Effects of probiotics on the recurrence of bacterial vaginosis: a review. J Low Genit Tract Dis. 2014;18(1):79–86.
Vicariotto F, Mogna L, Del Piano M. Effectiveness of the two microorganisms Lactobacillus fermentum LF15 and Lactobacillus plantarum LP01, formulated in slow-release vaginal tablets, in women affected by bacterial vaginosis: a pilot study. J Clin Gastroenterol. 2014;48(Suppl 1):106–12.
Saunders S, Bocking A, Challis J, Reid G. Effect of Lactobacillus challenge on Gardnerella vaginalis biofilms. Colloids Surf B Biointerfaces. 2007;55(2):138–42.
Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst Rev. 2009. doi:10.1002/14651858.
Mirmonsef P, Zariffard MR, Gilbert D, Makinde H, Landay AL, Spear GT. Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands. Am J Reprod Immunol. 2012;67(5):391–400.
Bradshaw CS, Pirotta M, De Guingand D, Hocking JS, Morton AN, Garland SM, et al. Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial. PLoS One. 2012;7:4.
Antonio MA, Meyn LA, Murray PJ, Busse B, Hillier SL. Vaginal colonization by probiotic Lactobacillus crispatus CTV-05 is decreased by sexual activity and endogenous Lactobacilli. J Infect Dis. 2009;199(10):1506–13.
Acknowledgements
I would like to acknowledge Keren Cooper, University of Cape Town for proofreading the manuscript before submission.
Competing interests
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Woodman, Z. Can one size fit all? Approach to bacterial vaginosis in sub-Saharan Africa. Ann Clin Microbiol Antimicrob 15, 16 (2016). https://doi.org/10.1186/s12941-016-0132-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12941-016-0132-6