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1.  IL-22 and IDO1 Affect Immunity and Tolerance to Murine and Human Vaginal Candidiasis 
PLoS Pathogens  2013;9(7):e1003486.
The ability to tolerate Candida albicans, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in IL22 and IDO1 genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.
Author Summary
This study disentangles resistance and tolerance components of murine and human C. albicans vaginal infection and introduces the challenging notion of a disease due to a defective tolerance mechanism. Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) are two forms of disease that affect a large number of otherwise healthy women. Uncomplicated VVC is associated with several predisposing factors, whereas RVVC, marked by idiopathic recurrent episodes, may be virtually untreatable. Despite a growing list of recognized risk factors, further understanding of anti-Candida host defense mechanisms in the vagina is needed to optimize vaccine development and immune interventions to integrate with, or even replace, antifungal therapy. Indeed, medical treatments that increase host resistance, such as antifungals, are highly effective for individual symptomatic attacks but do not prevent recurrences and there is concern that repeated treatments might induce drug resistance. As tolerance mechanisms are not expected to have the same selective pressure on pathogens, new drugs that target tolerance will provide therapies to which low-virulence pathogens, such as C. albicans, will not develop resistance. This study provides a proof-of-concept that targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.
doi:10.1371/journal.ppat.1003486
PMCID: PMC3708875  PMID: 23853597
2.  Probiotic lactobacillus and estrogen effects on vaginal epithelial gene expression responses to Candida albicans 
Background
Vaginal epithelial cells have receptors, signal transduction mechanisms, and cytokine secretion capabilities to recruit host defenses against Candida albicans infections. This research evaluates how probiotic lactobacilli affect the defensive epithelial response.
Methods
This study used quantitative reverse transcription-polymerase chain reaction assay (qRT-PCR), flow cytometry, and a multiplex immunoassay to observe changes in the regulation of gene expression related to cytokine responses in the VK2 (E6/E7) vaginal epithelial cell line treated with 17β-estradiol, exposed to probiotic Lactobacillus rhamnosus GR-1® and Lactobacillus reuteri RC-14® and challenged with C. albicans. Data were statistically evaluated by repeated measures analysis of variance and paired t-tests where appropriate.
Results
C. albicans induced mRNA expression of genes related to inflammatory cytokine responses associated with nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signal transduction pathways. 17β-estradiol suppressed expression of interleukin-1α (IL-1α), IL-6, IL-8, and tumor necrosis factor alpha (TNFα) mRNA. Probiotic lactobacilli suppressed C. albicans-induced nuclear factor-kappa B inhibitor kinase kinase alpha (Iκκα), Toll-like receptor-2 (TLR2), TLR6, IL-8, and TNFα, also suggesting inhibition of NF-κB signaling. The lactobacilli induced expression of IL-1α, and IL-1β mRNA, which was not inhibited by curcumin, suggesting that they induce an alternate inflammatory signal transduction pathway to NF-κB, such as the mitogen activated protein kinase and activator protein-1 (MAPK/AP-1) signal transduction pathway. Curcumin inhibited IL-13 secretion, suggesting that expression of this cytokine is mainly regulated by NF-κB signaling in VK2 cells.
Conclusions
The results suggest that C. albicans infection induces pro-inflammatory responses in vaginal epithelial cells, and estrogen and lactobacilli suppress expression of NF-κB-related inflammatory genes. Probiotic lactobacilli may induce IL-1α and IL-1β expression by an alternate signal transduction pathway, such as MAPK/AP-1. Activation of alternate signaling mechanisms by lactobacilli to modify epithelial cell cytokine production may be a mechanism for probiotic modulation of morbidity in vulvovaginal candidiasis.
doi:10.1186/1423-0127-19-58
PMCID: PMC3404894  PMID: 22715972
Probiotic; Epithelial cells; Gene expression; Signal transduction genes; Candidiasis; Estrogen
3.  Vulvovaginal candidiasis in Mato Grosso, Brazil: pregnancy status, causative species and drugs tests 
Brazilian Journal of Microbiology  2011;42(4):1300-1307.
Causative agent in majority of VVC is Candida albicans, but infection due to non-C. albicans is common. Use of empiric antifungal therapy in Brazil due to syndromic management of vulvovaginitis could act as risk factor for increase resistance among VVC causative agents. From Mato Grosso patients, 160 with culture-proved among 404 women who had clinical symptoms of VVC, were enrolled in this study. 70 non-pregnant women and 90 pregnant women were included. Candida albicans was the most prevalent, representing 72.9% in the non-pregnant group and 92.3% in the pregnant group. Differences in species distribution were noted between the two groups, being C. parapsilosis the second more prevalent species among non-pregnant women. Susceptibility testing revealed high susceptibility to fluconazole (except for C. krusei), itraconazole, ketoconazole, and amphotericin B regardless the species (C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, C. krusei) analyzed.
doi:10.1590/S1517-83822011000400009
PMCID: PMC3768752  PMID: 24031756
Vulvovaginal candidiasis; antifungal susceptibility testing; antifungal agents; Candida albicans
4.  Antifungal Activity of Brazilian Propolis Microparticles against Yeasts Isolated from Vulvovaginal Candidiasis 
Propolis, a resinous compound produced by Apis mellifera L. bees, is known to possess a variety of biological activities and is applied in the therapy of various infectious diseases. The aim of this study was to evaluate the in vitro antifungal activity of propolis ethanol extract (PE) and propolis microparticles (PMs) obtained from a sample of Brazilian propolis against clinical yeast isolates of importance in the vulvovaginal candidiasis (VVC). PE was used to prepare the microparticles. Yeast isolates (n = 89), obtained from vaginal exudates of patients with VVC, were exposed to the PE and the PMs. Moreover, the main antifungal drugs used in the treatment of VVC (Fluconazole, Voriconazole, Itraconazole, Ketoconazole, Miconazole and Amphotericin B) were also tested. Minimum inhibitory concentration (MIC) was determined according to the standard broth microdilution method. Some Candida albicans isolates showed resistance or dose-dependent susceptibility for the azolic drugs and Amphotericin B. Non-C. albicans isolates showed more resistance and dose-dependent susceptibility for the azolic drugs than C. albicans. However, all of them were sensitive or dose-dependent susceptible for Amphotericin B. All yeasts were inhibited by PE and PMs, with small variation, independent of the species of yeast. The overall results provided important information for the potential application of PMs in the therapy of VVC and the possible prevention of the occurrence of new symptomatic episodes.
doi:10.1093/ecam/neq029
PMCID: PMC3094883  PMID: 21607012
5.  In vivo activity of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida species 
Background
Study of in vivo antifungal activity of the hydroalcoholic extract (HE) and n-BuOH extract (BUTE) of Sapindus saponaria against azole-susceptible and -resistant human vaginal Candida spp.
Methods
The in vitro antifungal activity of HE, BUTE, fluconazole (FLU), and itraconazole (ITRA) was determined by the broth microdilution method. We obtained values of minimal inhibitory concentration (MIC) and minimum fungicide concentration (MFC) for 46 strains of C. albicans and 10 of C. glabrata isolated from patients with vulvovaginal candidiasis (VVC). VVC was induced in hyperestrogenic Wistar rats with azole-susceptible C. albicans (SCA), azole-resistant C. albicans (RCA), and azole-resistant C. glabrata (RCG). The rats were treated intravaginally with 0.1 mL of HE or BUTE at concentrations of 1%, 2.5% and 5%; 100 μg/mL of FLU (treatment positive control); or distilled water (negative control) at 1, 24, and 48 h after induction of the infection, and the progress of VVC was monitored by culturing and scanning electron microscopy (SEM). The toxicity was evaluated in cervical cells of the HeLa cell line.
Results
The extracts showed in vitro inhibitory and fungicidal activity against all the isolates, and the MIC and MFC values for the C. glabrata isolates were slightly higher. In vivo, the SCA, RCA, and RCG infections were eliminated by 21 days post-infection, with up to 5% HE and BUTE, comparable to the activity of FLU. No cytotoxic action was observed for either extract.
Conclusions
Our results demonstrated that HE and BUTE from S. saponaria show inhibitory and fungicidal activity in vitro, in addition to in vivo activity against azole-resistant vaginal isolates of C. glabrata and azole-susceptible and resistant isolates of C. albicans. Also considering the lack of cytotoxicity and the low concentrations of the extracts necessary to eliminate the infection in vivo, HE and BUTE show promise for continued studies with purified antifungal substances in VVC yeast isolates.
doi:10.1186/1472-6882-11-35
PMCID: PMC3097010  PMID: 21542936
Sapindus saponaria; vaginal yeasts; antifungal activity; in vivo
6.  Effects of Reproductive Hormones on Experimental Vaginal Candidiasis 
Infection and Immunity  2000;68(2):651-657.
Vulvovaginal candidiasis (VVC) is an opportunistic mucosal infection caused by Candida albicans that affects large numbers of otherwise healthy women of childbearing age. Acute episodes of VVC often occur during pregnancy and during the luteal phase of the menstrual cycle, when levels of progesterone and estrogen are elevated. Although estrogen-dependent experimental rodent models of C. albicans vaginal infection are used for many applications, the role of reproductive hormones and/or their limits in the acquisition of vaginal candidiasis remain unclear. This study examined the effects of estrogen and progesterone on several aspects of an experimental infection together with relative cell-mediated immune responses. Results showed that while decreasing estrogen concentrations eventually influenced infection-induced vaginal titers of C. albicans and rates of infection in inoculated animals, the experimental infection could not be achieved in mice treated with various concentrations of progesterone alone. Furthermore, progesterone had no effect on (i) the induction and persistence of the infection in the presence of estrogen, (ii) delayed-type hypersensitivity in primary-infected mice, or (iii) the partial protection from a secondary vaginal infection under pseudoestrus conditions. Other results with estrogen showed that a persistent infection could be established with a wide range of C. albicans inocula under supraphysiologic and near-physiologic (at estrus) concentrations of estrogen and that vaginal fungus titers or rates of infection were similar if pseudoestrus was initiated several days before or after inoculation. However, the pseudoestrus state had to be maintained for the infection to persist. Finally, estrogen was found to reduce the ability of vaginal epithelial cells to inhibit the growth of C. albicans. These results suggest that estrogen, but not progesterone, is an important factor in hormone-associated susceptibility to C. albicans vaginitis.
PMCID: PMC97188  PMID: 10639429
7.  Effect of pH on In Vitro Susceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use 
The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH, C. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90 for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0.
doi:10.1128/AAC.05025-11
PMCID: PMC3294902  PMID: 22232293
8.  Clinical Characteristics of Turkish Women with Candida krusei Vaginitis and Antifungal Susceptibility of the C. krusei Isolates  
Objective. Candida krusei causes approximately 1% of vulvovaginal candidiasis (VVC) cases and is naturally resistant to fluconazole. Antifungal testing may be required if C. krusei vaginitis fails to respond to non-fluconazole therapy, particularly in patients with recurrent infections. Design. We investigated the clinical characteristics and antifungal susceptibility profile of vaginal C. krusei isolates. Between 2009 and 2012, we identified 560 unrelated Candida spp.-positive vaginal cultures, of which 28 (5.0%) were C. krusei. These isolates were analyzed according to host factors and the clinical forms of VVC, and their in vitro susceptibility to 10 antifungal agents was tested using a reference microdilution method. Results. We observed that perineal laceration and increased age (>50 years) were significant predictors of C. krusei in vaginal samples (P < 0.05). All isolates were susceptible to amphotericin B, caspofungin, ketoconazole, and miconazole. Additionally, susceptible dose-dependent and resistant rates were found for fluconazole as 42.9% and 57.1%, respectively. Remarkably, only 42.9% and 67.9% of the isolates were susceptible to itraconazole and voriconazole, respectively. Conclusions. Understanding local susceptibility patterns, especially those of non-C. albicans Candida species, can significantly aid in the selection of an effective antifungal agent. The in vivo response of C. krusei vaginitis to various antifungal therapeutics remains unknown and requires further research.
doi:10.1155/2013/698736
PMCID: PMC3874352  PMID: 24396265
9.  Clotrimazole Dampens Vaginal Inflammation and Neutrophil Infiltration in Response to Candida albicans Infection 
Antimicrobial Agents and Chemotherapy  2013;57(10):5178-5180.
The pathology of vulvovaginal candidiasis (VVC) caused by Candida albicans is associated with a nonprotective inflammatory response and is frequently treated with clotrimazole. We investigated the mechanisms by which clotrimazole resolves VVC. Low levels of clotrimazole, which do not block fungal growth, inhibit expression of a “danger response” transcription factor, c-Fos, block production of proinflammatory cytokines, and inhibit neutrophil infiltration to the site of infection.
doi:10.1128/AAC.01244-13
PMCID: PMC3811401  PMID: 23896471
10.  Susceptibility Pattern of Various Azoles Against Candida Species Causing Vulvovaginal Candidiasis 
Objectives
Vulvovaginal candidiasis (VVC) is a common gynecological finding among the women worldwide. Candida species are often less susceptible to antifungal agents. Owing to this fact, in this study, we aimed at assessing the prevalence rate and antimicrobial susceptibility pattern of various azoles against Candida species causing VVC in symptomatic women.
Methods
The prospective study included 217 female patients with symptoms of vaginal discharges. Specimens were characterized microscopically and were subjected to antimicrobial susceptibility testing against various azoles according to NCCLSM44 disk-diffusion method.
Results
VVC was detected in 18.4 % of the cases. Based on age distribution, the highest rate of Candida infection was observed in the age group of 20–29 years (42.5 %). Antifungal susceptibility revealed that fluconazole was highly effective against Candida Species (97.2 %); on the contrary, the highest resistance was observed in the case of miconazole (63 %).
Conclusion
In the current study, prevalence rate of VVC was found to be 18.4 %, and among the various azoles tested, fluconazole has the highest antimicrobial activity.
doi:10.1007/s13224-012-0280-3
PMCID: PMC3664691  PMID: 24431621
Vulvovaginal candidiasis; Fluconazole; Miconazole
11.  Biotherapeutic effects of probiotic bacteria on candidiasis in immunodeficient mice. 
Infection and Immunity  1997;65(10):4165-4172.
Four species of probiotic bacteria were assessed for their capacities to protect athymic bg/bg-nu/nu and euthymic bg/bg-nu/+ mice from mucosal and systemic candidiasis. Each bacterial species and Candida albicans colonized the gastrointestinal tracts of both strains of mice. The presence of probiotic bacteria (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei GG, or Bifidobacterium animalis) in the gastrointestinal tracts prolonged the survival of adult and neonatal bg/bg-nu/nu mice compared to that of isogenic mice colonized with C. albicans alone. The incidence of systemic candidiasis in bg/bg-nu/nu mice was significantly reduced by each of the four probiotic bacterial species. The numbers of C. albicans present in the alimentary tracts of euthymic bg/bg-nu/+ mice were significantly reduced by L. casei GG and B. animalis. None of the probiotic bacteria species completely prevented mucosal candidiasis, but B. animalis reduced its incidence and severity. Probiotic bacteria also modulated antibody- and cell-mediated immune responses to C. albicans. The prolonged survival of mice, decreased severity of mucosal and systemic candidiasis, modulation of immune responses, decreased number of C. albicans in the alimentary tract, and reduced numbers of orogastric infections demonstrated not only that probiotic bacteria have biotherapeutic potential for prophylaxis against and therapy of this fungal disease but also that probiotic bacteria protect mice from candidiasis by a variety of immunologic (thymic and extrathymic) and nonimmunologic mechanisms in this model.
PMCID: PMC175599  PMID: 9317023
12.  Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome 
Journal of Perinatology  2010;31(1):63-69.
Objective:
To evaluate the efficacy of probiotics in the prevention of gastrointestinal colonization by Candida species, of late-onset sepsis and neurological outcome in preterm newborns.
Study Design:
A prospective study was conducted in 249 preterms who were subdivided into three groups: one group (n=83) was supplemented with Lactobacillus (L.) reuteri, one group with L. rhamnosus (n=83) and the other with no supplementation (n=83). The fungal colonization in the gastrointestinal tract, the late onset of sepsis and clinical parameters were recorded. A neurological structured assessment was further performed at 1 year of age.
Result:
Candida stool colonization was significantly higher (P<0.01) in the control group than in the groups treated with probiotics. The L. reuteri group presented a significantly higher reduction in gastrointestinal symptoms than did the L. rhamnosus and control groups. Infants treated with probiotics showed a statistically significant lower incidence of abnormal neurological outcome than did the control group.
Conclusion:
The use of both probiotics seems to be effective in the prevention of gastrointestinal colonization by Candida, in the protection from late-onset sepis and in reducing abnormal neurological outcomes in preterms.
doi:10.1038/jp.2010.57
PMCID: PMC3016918  PMID: 20410904
probiotics; preterms; neurological assessment
13.  Use of Antifungal Saponin SC-2 of Solanum Chrysotrichum for the Treatment of Vulvovaginal Candidiasis: In Vitro Studies and Clinical Experiences 
Saponin SC-2 from Solanum chrysotrichum showed antifungal activity, demonstrated in vitro, which inhibited the growth of dermatophytes, and in vivo, to be effective in the treatment against tinea pedis and pityriasis capitis. Fungistatic and fungicidal activity of saponin SC-2 on Candida albicans and other Candida species, fluconazole and ketoconazole resistaent strains was demostrated. SC-2-associated ultrastructural alterations in several Candida species were observed. An exploratory clinical, randomized, double-blind, and controlled ketoconazole study of ketoconazole was conducted with the aim of assessing the effectiveness and tolerability of an herbal medicinal product containing SC-2, on women with Vulvovaginal candidiasis (VVC). The results exhibited a percentage of therapeutic clinical effectiveness similar to that of ketoconazole (X2, p ≥0.30), but obtained a smaller percentage of mycological effectiveness, and 100% tolerability. In conclusion, saponin SC-2 possesses fungicidale and fungistatic activity on Candida albicans and other multi resistant Candida species, causes morphological changes and fungal death, and it is an alternative therapy for the treatment of VVC.
PMCID: PMC3777579  PMID: 24146467
Solanum chrysotrichum; saponins; antifungal activity; vulvovaginal candidiasis; alternative therapy
14.  An evaluation of butoconazole nitrate 2% site release vaginal cream (Gynazole-1) compared to fluconazole 150 mg tablets (Diflucan) in the time to relief of symptoms in patients with vulvovaginal candidiasis. 
BACKGROUND: It is estimated that as many as 13 million cases of vulvovaginal infection occur in the United States annually, the majority of which are the result of Candida albicans infection. The symptoms of vulvovaginal infections are often painful and distressing to the patient. The objective of this study was to compare the time to symptomatic relief of vulvovaginal candidiasis (VVC) with butoconazole nitrate 2% Site Release vaginal cream (Gynazole-1) and oral fluconazole 150 mg tablets (Diflucan). METHODS: This randomized, open-label, parallel study evaluated 181 female patients with moderate to severe symptoms of VVC. Patients were randomized to single-dose therapy with either butoconazole nitrate 2% Site Release vaginal cream or fluconazole. The primary outcome measure was the time to onset of first relief of symptoms. Secondary measures included the time to overall relief of symptoms and the reinfection rate over the first 30 days following treatment. The overall safety of both products was investigated through the collection of adverse event reports. RESULTS: The median time to first relief of symptoms occurred at 17.5 h for butoconazole patients as compared to 22.9 h for fluconazole patients (p < 0.001). The time at which 75% of patients experienced first relief of symptoms was 24.5 h versus 46.3 h for butoconazole and fluconazole, respectively (p < 0.001). By 12- and 24-h post-treatment, 44.4% and 72.8% of patients in the butoconazole treatment group reported first relief of symptoms versus 29.1% and 55.7% of patients in the fluconazole group (p = 0.044 and p = 0.024 respectively). In patients experiencing first relief of symptoms within 48 h of dosing, the median time to first relief of symptoms in the butoconazole treatment group was significantly shorter at 12.9 h compared to 20.7 h for the fluconazole treatment group (p = 0.048). There were no significant differences between the two groups with respect to time to total relief of symptoms or reoccurrence of infection within 30 days of treatment. Butoconazole therapy was shown to have fewer reported adverse events, including drug-related adverse events, than fluconazole therapy. Vulvovaginal pruritis and vulvovaginal burning were the most common drug-related adverse events attributed to butoconazole. Headache, diarrhea, nausea, upset stomach and skin sensitivity were the most common drug-related adverse events attributable to fluconazole. CONCLUSIONS: Single-dose butoconazole nitrate 2% Site Release vaginal cream provides statistically significant improvement in time to first relief of symptoms in the treatment of VVC compared to fluconazole. There is no difference between these two treatments with respect to total relief of symptoms or reinfection rate. Although there was no significant difference in the incidence of adverse events judged by the investigator to be treatment-related, butoconazole treatment did result in fewer patients experiencing adverse events than fluconazole.
doi:10.1080/10647440500240615
PMCID: PMC1784583  PMID: 16338779
15.  Genital Candida Species Detected in Samples from Women in Melbourne, Australia, before and after Treatment with Antibiotics 
Journal of Clinical Microbiology  2006;44(9):3213-3217.
Vulvovaginal candidiasis (VVC) remains a common cause of morbidity, with three-quarters of women affected during their lifetimes. Use of antibiotics is an acknowledged trigger for VVC, which adversely affects women's physical and emotional health. Knowledge of patterns of genital Candida species-level identification is important for management, as Candida species other than Candida albicans often fail first-line treatment. A community sample of women with no vaginal symptoms, and who were prescribed antibiotics, was recruited into this study, where the incidence of genital colonization by various Candida species was documented, as well as symptoms of VVC plus relevant associations, before and after treatment with antibiotics. Self-collected low vaginal swabs were taken prior to and 8 days after completion of antibiotic treatment, and data on various potential risk factors for VVC were collected simultaneously, with complete data being available for 233 participants. Baseline Candida species colonization was present in 21% of women (95% confidence intervals [CI], 17% to 27%), rising to 37% (95% CI, 31% to 44%) after antibiotic treatment. The primary species detected for either period was C. albicans (73%), with Candida glabrata detected in around 20%. Self-assessed proneness to VVC after antibiotic treatment and baseline colonization with Candida spp. were significantly associated with symptomatic VVC after antibiotic treatment. For microbiologically proven candidiasis, VVC symptoms had a sensitivity of 57% and a specificity of 91%. When physicians prescribe antibiotics, the history of risk of VVC is one issue that physicians should discuss with women, particularly those who are self-identified as being prone to VVC. Furthermore, we recommend that definitive microbiological diagnoses be made for women with recurrent symptoms or those failing initial treatment, to guide appropriate therapy.
doi:10.1128/JCM.00218-06
PMCID: PMC1594690  PMID: 16954250
16.  Strain-Dependent Augmentation of Tight-Junction Barrier Function in Human Primary Epidermal Keratinocytes by Lactobacillus and Bifidobacterium Lysates 
Applied and Environmental Microbiology  2013;79(16):4887-4894.
In this study, we investigated whether probiotic lysates can modify the tight-junction function of human primary keratinocytes. The keratinocytes were grown on cell culture inserts and treated with lysates from Bifidobacterium longum, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus fermentum, or Lactobacillus rhamnosus GG. With the exception of L. fermentum (which decreased cell viability), all strains markedly enhanced tight-junction barrier function within 24 h, as assessed by measurements of transepithelial electrical resistance (TEER). However, B. longum and L. rhamnosus GG were the most efficacious, producing dose-dependent increases in resistance that were maintained for 4 days. These increases in TEER correlated with elevated expression of tight-junction protein components. Neutralization of Toll-like receptor 2 abolished both the increase in TEER and expression of tight-junction proteins induced by B. longum, but not L. rhamnosus GG. These data suggest that some bacterial strains increase tight-junction function via modulation of protein components but the different pathways involved may vary depending on the bacterial strain.
doi:10.1128/AEM.00982-13
PMCID: PMC3754719  PMID: 23770906
17.  The Acute Neutrophil Response Mediated by S100 Alarmins during Vaginal Candida Infections Is Independent of the Th17-Pathway 
PLoS ONE  2012;7(9):e46311.
Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19−/−, IL-17RA−/− and IL-22−/− mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.
doi:10.1371/journal.pone.0046311
PMCID: PMC3457984  PMID: 23050010
18.  An Intravaginal Live Candida Challenge in Humans Leads to New Hypotheses for the Immunopathogenesis of Vulvovaginal Candidiasis  
Infection and Immunity  2004;72(5):2939-2946.
Acute and recurrent vulvovaginal candidiasis (VVC) remains a significant problem in women of childbearing age. While clinical studies of women with recurrent VVC (RVVC) and animal models have provided important data about a limited protective role of adaptive immunity, there remains a paucity of information on the protective mechanisms or factors associated with susceptibility to infection. In the present study, an intravaginal live Candida challenge in healthy adult women showed a differential susceptibility to symptomatic VVC, where 3 (15%) of 19 women with no history of VVC acquired a symptomatic infection compared to 6 (55%) of 11 women with an infrequent history of VVC. Furthermore, these studies revealed that protection against infection is noninflammatory while symptomatic infection correlates with a vaginal infiltration of polymorphonuclear neutrophils (PMNs) and a high vaginal fungal burden. Thus, the presence of symptomatic infection appears more dependent on host factors than on properties of the organism. Finally, vaginal lavage fluid from women with a symptomatic infection, but not those asymptomatically colonized, promoted the chemotaxis of PMNs. These results suggest that rather than RVVC/VVC being caused by an aberrant adaptive immune response, symptoms that define infection appear to be due to an aggressive innate response by PMNs.
doi:10.1128/IAI.72.5.2939-2946.2004
PMCID: PMC387876  PMID: 15102806
19.  Adhesion of Human Probiotic Lactobacillus rhamnosus to Cervical and Vaginal Cells and Interaction with Vaginosis-Associated Pathogens 
Objectives. The ability of a probiotic Lactobacillus rhamnosus strain (Lcr35) to adhere to cervical and vaginal cells and to affect the viability of two main vaginosis-associated pathogens, Prevotella bivia, Gardnerella vaginalis, as well as Candida albicans was investigated. Methods. Adhesion ability was determined in vitro with immortalized epithelial cells from the endocervix, ectocervix, and vagina. Coculture experiments were performed to count viable pathogens cells in the presence of Lcr35. Results. Lcr35 was able to specifically and rapidly adhere to the three cell lines. In coculture assays, a decrease in pathogen cell division rate was observed as from 4 hours of incubation and bactericidal activity after a longer period of incubation, mostly with P. bivia. Conclusion. The ability of Lcr35 to adhere to cervicovaginal cells and its antagonist activities against vaginosis-associated pathogens suggest that this probiotic strain is a promising candidate for use in therapy.
doi:10.1155/2008/549640
PMCID: PMC2631649  PMID: 19190778
20.  Genome-Wide Expression Profile Analysis Reveals Coordinately Regulated Genes Associated with Stepwise Acquisition of Azole Resistance in Candida albicans Clinical Isolates 
Candida albicans is an opportunistic human fungal pathogen and a causative agent of oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients with AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents treatment failures have occurred. Such failures have been associated with the emergence of azole-resistant strains of C. albicans. In the present study we examined changes in the genome-wide gene expression profile of a series of C. albicans clinical isolates representing the stepwise acquisition of azole resistance. In addition to genes previously associated with azole resistance, we identified many genes whose differential expression was for the first time associated with this phenotype. Furthermore, the expression of these genes was correlated with that of the known resistance genes CDR1, CDR2, and CaMDR1. Genes coordinately regulated with the up-regulation of CDR1 and CDR2 included the up-regulation of GPX1 and RTA3 and the down-regulation of EBP1. Genes coordinately regulated with the up-regulation of CaMDR1 included the up-regulation of IFD1, IFD4, IFD5, IFD7, GRP2, DPP1, CRD2, and INO1 and the down-regulation of FET34, OPI3, and IPF1222. Several of these appeared to be coordinately regulated with both the CDR genes and CaMDR1. Many of these genes are involved in the oxidative stress response, suggesting that reduced susceptibility to oxidative damage may contribute to azole resistance. Further evaluation of the role these genes and their respective gene products play in azole antifungal resistance is warranted.
doi:10.1128/AAC.47.4.1220-1227.2003
PMCID: PMC152536  PMID: 12654650
21.  Analysis of Vaginal Lactobacilli from Healthy and Infected Brazilian Women▿ †  
Applied and Environmental Microbiology  2008;74(14):4539-4542.
Culture-dependent PCR-amplified rRNA gene restriction analysis and culture-independent (PCR-denaturing gradient gel electrophoresis) methodologies were used to examine vaginal lactobacilli from Brazilian women who were healthy or had been diagnosed with vulvovaginal candidiasis (VVC) or bacterial vaginosis. Only Lactobacillus crispatus was detected accordingly by both methods, and H2O2-producing lactobacilli were not associated with protection against VVC.
doi:10.1128/AEM.00284-08
PMCID: PMC2493183  PMID: 18502927
22.  Usage of antifungal drugs for therapy of genital Candida infections, purchased as over-the-counter products or by prescription: I. Analyses of a unique database. 
OBJECTIVES: To present sales figures of antifungal drugs for treatment of genital Candida infections in females, which had been purchased in the Swedish county of Skåne (with approximately 1.2 million inhabitants) during the 1990s. To study the relative proportions of the drugs sold by prescription and as over-the-counter (OTC) products. METHODS: Sales figures of antifungal drugs for therapy of vulvovaginal candidiasis (VVC) and such recurrent infections (RVVC), for the years 1990--99, were collected from the 'ACS' database of the National Corporation of Swedish Pharmacies. RESULTS: The study showed an increase in sales of the type of drugs studied from 45,000 packages in 1990 until mid-93/94, when approximately 70,000 packages were sold (mainly azoles for topical use and fluconazole for oral intake). Thereafter there was a decrease until the end of November 1999, when 54,000 packages were purchased. Of the total sales, 93% were OTC products. Sales of clotrimazole and econazole (for vaginal installation) in 1993--1994 were equal to 85-90 packages/1000 women in the age group 15-45 years. Extremely high sales volumes of fluconazole and itraconazole, for one single year each, could be explained by marketing-related activities directed to the medical community. CONCLUSIONS: As many women with RVVC are not cured by iatrogenic initiatives and women consider themselves able to diagnose episodes of genital Candida infection, affected women generally turn to self-medication with antifungal OTC products. This stresses the role of pharmacy counseling. Short-term marked alterations in sales volumes may be due to marketing factors rather than changes in the epidemiology of genital Candida infections.
PMCID: PMC1784597  PMID: 15739823
23.  New Approaches in the Development of a Vaccine for Mucosal Candidiasis: Progress and Challenges 
The commensal fungus Candida albicans causes mucosal candidiasis in the rapidly expanding number of immunocompromised patients. Mucosal candidiasis includes oropharyngeal, esophageal, gastrointestinal, and vaginal infections. Vulvovaginal candidiasis (VVC) and antimycotic-refractory recurrent VVC is a frequent problem in healthy childbearing women. Both these mucosal infections can affect the quality of life and finding new therapeutical and preventive approaches is a challenge. A vaccine against candidal infections would be a new important tool to prevent and/or cure mucosal candidiasis and would be of benefit to many patients. Several Candida antigens have been proposed as vaccine candidates including cell wall components and virulence factors. Here we discuss the recent progress and problems associated with vaccination against mucosal candidiasis.
doi:10.3389/fmicb.2012.00294
PMCID: PMC3417234  PMID: 22905033
mucosal candidiasis; C. albicans; vaccine; fungal infections; candidiasis
24.  Role for Dendritic Cells in Immunoregulation during Experimental Vaginal Candidiasis  
Infection and Immunity  2006;74(6):3213-3221.
Vulvovaginal candidiasis (VVC) caused by the commensal organism Candida albicans remains a significant problem among women of childbearing age, with protection against and susceptibility to infection still poorly understood. While cell-mediated immunity by CD4+ Th1-type cells is protective against most forms of mucosal candidiasis, no protective role for adaptive immunity has been identified against VVC. This is postulated to be due to immunoregulation that prohibits a more profound Candida-specific CD4+ T-cell response against infection. The purpose of this study was to examine the role of dendritic cells (DCs) in the induction phase of the immune response as a means to understand the initiation of the immunoregulatory events. Immunostaining of DCs in sectioned murine lymph nodes draining the vagina revealed a profound cellular reorganization with DCs becoming concentrated in the T-cell zone throughout the course of experimental vaginal Candida infection consistent with cell-mediated immune responsiveness. However, analysis of draining lymph node DC subsets revealed a predominance of immunoregulation-associated CD11c+ B220+ plasmacytoid DCs (pDCs) under both uninfected and infected conditions. Staining of vaginal DCs showed the presence of both DEC-205+ and pDCs, with extension of dendrites into the vaginal lumen of infected mice in close contact with Candida. Flow cytometric analysis of draining lymph node DC costimulatory molecules and activation markers from infected mice indicated a lack of upregulation of major histocompatibility complex class II, CD80, CD86, and CD40 during infection, consistent with a tolerizing condition. Together, the results suggest that DCs are involved in the immunoregulatory events manifested during a vaginal Candida infection and potentially through the action of pDCs.
doi:10.1128/IAI.01824-05
PMCID: PMC1479243  PMID: 16714548
25.  Vaginal yeast colonisation, prevalence of vaginitis, and associated local immunity in adolescents 
Objectives: To evaluate point prevalence vaginal yeast colonisation and symptomatic vaginitis in middle adolescents and to identify relation of these yeast conditions with reproductive hormones, sexual activity, sexual behaviours, and associated local immunity.
Methods: Middle adolescent females (n = 153) were evaluated for sexually transmitted infections (STIs), asymptomatic yeast colonisation, and symptomatic vulvovaginal candidiasis (VVC) by standard criteria. Also evaluated were local parameters, including vaginal associated cytokines, chemokines, and antibodies, vaginal epithelial cell antifungal activity, and Candida specific peripheral blood lymphocyte responses. Correlations between yeast colonisation/vaginitis and local immunomodulators, reproductive hormones, douching, sexual activity, condom use, and STIs were identified.
Results: Rates of point prevalence asymptomatic yeast colonisation (22%) were similar to adults and similarly dominated by Candida albicans, but with uncharacteristically high vaginal yeast burden. In contrast with the high rate of STIs (18%), incidence of symptomatic VVC was low (<2%). Immunological properties included high rates of Candida specific systemic immune sensitisation, a Th2 type vaginal cytokine profile, total and Candida specific vaginal antibodies dominated by IgA, and moderate vaginal epithelial cell anti-Candida activity. Endogenous reproductive hormones were in low concentration. Sexual activity positively correlated with vaginal yeast colonisation, whereas vaginal cytokines (Th1, Th2, proinflammatory), chemokines, antibodies, contraception, douching, or condom use did not.
Conclusion: Asymptomatic vaginal yeast colonisation in adolescents is distinct in some ways with adults, and positively correlates with sexual activity, but not with local immunomodulators or sexual behaviours. Despite several factors predictive for VVC, symptomatic VVC was low compared to STIs.
doi:10.1136/sti.2002.003855
PMCID: PMC1758371  PMID: 14755036

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