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Journal of the Turkish German... May 2021
PubMed: 33663197
DOI: 10.4274/jtgga.galenos.2021.2020.0195 -
MBio Apr 2023The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity,...
The polymorphic fungus Candida albicans remains a leading cause of both invasive and superficial mycoses, including vulvovaginal candidiasis (VVC). Metabolic plasticity, including carbohydrate catabolism, confers fitness advantages at anatomical site-specific host niches. C. albicans possesses the capacity to accumulate and store carbohydrates as glycogen and can consume intracellular glycogen stores when nutrients become limited. In the vaginal environment, estrogen promotes epithelial glycogen accumulation and C. albicans colonization. However, whether these factors are mechanistically linked is unexplored. Here, we characterized the glycogen metabolism pathways in C. albicans and investigated whether these impact the long-term survival of C. albicans, both and during murine VVC, or virulence during systemic infection. SC5314 and 6 clinical isolates demonstrated impaired growth when glycogen was used as the sole carbon source, suggesting that environmental glycogen acquisition is limited. The genetic deletion and complementation of key genes involved in glycogen metabolism in Saccharomyces cerevisiae confirmed that and , as well as and , are essential for glycogen synthesis and catabolism in C. albicans, respectively. Potential compensatory roles for a glucoamylase encoded by were also explored. Competitive survival assays revealed that , Δ/Δ, and mutants exhibited long-term survival defects under starvation conditions and during vaginal colonization. A complete inability to catabolize glycogen () also rendered C. albicans significantly less virulent during disseminated infections. This is the first study fully validating the glycogen metabolism pathways in C. albicans, and the results further suggest that intracellular glycogen catabolism positively impacts the long-term fitness of C. albicans in nutrient deficient environments and is important for full virulence. Glycogen is a highly branched polymer of glucose and is used across the tree of life as an efficient and compact form of energy storage. Whereas glycogen metabolism pathways have been studied in model yeasts, they have not been extensively explored in pathogenic fungi. Using a combination of microbiologic, molecular genetic, and biochemical approaches, we reveal orthologous functions of glycogen metabolism genes in the fungal pathogen Candida albicans. We also provide evidence that extracellular glycogen poorly supports growth across the species and clinical isolates. Competitive fitness assays reveal that the loss of glycogen synthesis or catabolism significantly impacts survival during both starvation and the colonization of the mouse vagina. Moreover, a global glycogen catabolism mutant is rendered less virulent during murine invasive candidiasis. Therefore, this work demonstrates that glycogen metabolism in C. albicans contributes to survival and virulence in the mammalian host and may be a novel antifungal target.
Topics: Female; Humans; Animals; Mice; Candida albicans; Virulence; Candidiasis, Vulvovaginal; Antifungal Agents; Candidiasis, Invasive; Glycogen; Mammals
PubMed: 36840583
DOI: 10.1128/mbio.00046-23 -
Journal of Fungi (Basel, Switzerland) Oct 2018species are one of the commonest causes of vaginitis in healthy women of reproductive age. Vulvovaginal candidiasis (VVC) is characterized by vulvovaginal itching,... (Review)
Review
species are one of the commonest causes of vaginitis in healthy women of reproductive age. Vulvovaginal candidiasis (VVC) is characterized by vulvovaginal itching, redness and discharge. , which is a common genito-urinary tract commensal, has been the prominent species and remains the most common fungal agent isolated from clinical samples of patients diagnosed with VVC. In recent times, however, there has been a notable shift in the etiology of candidiasis with non- (NAC) species gaining prominence. The NAC species now account for approximately 10% to as high as 45% of VVC cases in some studies. This is associated with treatment challenges and a slightly different clinical picture. NAC species vaginitis is milder in presentation, often occur in patients with underlying chronic medical conditions and symptoms tend to be more recurrent or chronic compared with vaginitis. is the most common cause of NAC-VVC. , , , and are the other commonly implicated species. Treatment failure is common in NAC-VVC, since some of these species are intrinsically resistant or show low susceptibilities to commonly used antifungal agents. This article reviews the etiology, pathogenesis, clinical features, diagnosis, and management of NAC vulvovaginitis.
PubMed: 30384449
DOI: 10.3390/jof4040121 -
Germs Jun 2023Infectious vaginitis is prevalent in developing countries. Most of the females suffer from vaginal infections at least once per lifetime. Due to limited resources, many...
INTRODUCTION
Infectious vaginitis is prevalent in developing countries. Most of the females suffer from vaginal infections at least once per lifetime. Due to limited resources, many infections are misdiagnosed or undiagnosed. Good diagnosis of these infections is critically important and will definitely help to guide treatment and prevent recurrence.
METHODS
A total of 1080 vaginal swabs were collected from symptomatic females. Nugent's score and Amsel's criteria were applied to diagnose bacterial vaginosis (BV). A rapid test was used to identify . Trichomonal vaginitis (TV) was diagnosed through microscopic examination. Vulvovaginal candidiasis (VVC) was also identified microscopically and using conventional culture. Finally, aerobic vaginitis (AV) was detected using Donder's scale combined with conventional culture and biochemical tests.
RESULTS
There was no statistically significant association between age and type of vaginal infection (p=0.130). Vulvovaginal inflammation, itching and redness were significantly associated with VVC (p≤0.012). BV was detected as single infection in 43.8%, followed by VVC 24.2%. On the contrary, AV and TV were scarcely detected among the participants; 4.9% and 0.5% respectively. Mixed infections between BV and VVC were noted in 26.6%.
CONCLUSIONS
BV showed the highest prevalence followed by VVC. Mixed infections between BV and VVC were evidently noted, therefore good reliable diagnosis using cost-effective methods is crucial for proper treatment. Aerobic vaginitis showed low prevalence and most of the spp. were isolated from pregnant females. The low prevalence of may be due to the dependance on conventional methods for diagnosis, and thus more advanced diagnostic tools are required.
PubMed: 38144250
DOI: 10.18683/germs.2023.1376 -
MSystems Aug 2021Despite the strikingly high worldwide prevalence of vulvovaginal candidiasis (VVC), treatment options for recurrent VVC (RVVC) remain limited, with many women...
Despite the strikingly high worldwide prevalence of vulvovaginal candidiasis (VVC), treatment options for recurrent VVC (RVVC) remain limited, with many women experiencing failed clinical treatment with frontline azoles. Further, the cause of onset and recurrence of disease is largely unknown, with few studies identifying potential mechanisms of treatment failure. This study aimed to assess a panel of clinical samples from healthy women and those with RVVC to investigate the influence of , the vaginal microbiome, and how their interaction influences disease pathology. 16S rRNA sequencing characterized disease by a reduction in specific health-associated species, such as Lactobacillus crispatus, coupled with an increase in Lactobacillus iners. analysis showed that Candida albicans clinical isolates are capable of heterogeneous biofilm formation, and we found the presence of hyphae and C. albicans aggregates in vaginal lavage fluid. Additionally, the ability of to inhibit C. albicans biofilm formation and biofilm-related gene expression was demonstrated. Using RNA sequencing technology, we were able to identify a possible mechanism by which L. crispatus may contribute to re-establishing a healthy vaginal environment through amino acid acquisition from C. albicans. This study highlights the potential formation and impact of biofilms in RVVC. Additionally, it suggests that RVVC is not entirely due to an arbitrary switch in C. albicans from commensal to pathogen and that understanding interactions between this yeast and vaginal species may be crucial to elucidating the cause of RVVC and developing appropriate therapies. RVVC is a significant burden, both economically and for women's health, but its prevalence is poorly documented globally due to the levels of self-treatment. Identifying triggers for development and recurrence of VVC and the pathogenesis of the microbes involved could considerably improve prevention and treatment options for women with recurrent, azole-resistant cases. This study therefore aimed to examine the interkingdom dynamics from healthy women and those with RVVC using next-generation sequencing techniques and to further investigate the molecular interactions between C. albicans and L. crispatus in a relevant biofilm coculture system.
PubMed: 34374560
DOI: 10.1128/mSystems.00622-21 -
Pathogens (Basel, Switzerland) Oct 2015The widespread occurrence of vaginal candidiasis and the development of resistance against anti-fungal agents has stimulated interest in understanding the pathogenesis... (Review)
Review
The widespread occurrence of vaginal candidiasis and the development of resistance against anti-fungal agents has stimulated interest in understanding the pathogenesis of this disease. The aim of our work was to characterize, in an animal model of vaginal candidiasis, the mechanisms that play a role in the induction of mucosal immunity against C. albicans and the interaction between innate and adaptive immunity. Our studies evidenced the elicitation of cell-mediated immunity (CMIs) and antibody (Abs)-mediated immunity with a Th1 protective immunity. An immune response of this magnitude in the vagina was very encouraging to identify the proper targets for new strategies for vaccination or immunotherapy of vaginal candidiasis. Overall, our data provide clear evidence that it is possible to prevent C. albicans vaginal infection by active intravaginal immunization with aspartyl proteinase expressed as recombinant protein. This opens the way to a modality for anti-Candida protection at the mucosa. The recombinant protein Sap2 was assembled with virosomes, and a vaccine PEVION7 (PEV7) was obtained. The results have given evidence that the vaccine, constituted of virosomes and Secretory aspartyl proteinase 2 (Sap2) (PEV7), has an encouraging therapeutic potential for the treatment of recurrent vulvovaginal candidiasis.
PubMed: 26473934
DOI: 10.3390/pathogens4040697 -
Healthcare (Basel, Switzerland) Nov 2021An estimated 75% of women will have one episode of vulvovaginal candidiasis (VCC) during their lifetime, and 40-50% of these will experience further episodes. The high...
An estimated 75% of women will have one episode of vulvovaginal candidiasis (VCC) during their lifetime, and 40-50% of these will experience further episodes. The high incidence of vulvovaginal candidiasis, combined with the problems of azole resistance and toxicity, highlights the necessity for new strategies for the treatment of this condition. In this context, natural compounds represent promising alternatives. We enrolled, between January 2020 and April 2021, forty women affected by uncomplicated vulvovaginal candidiasis. Women were divided into two groups. In the first group, we treated 20 women with clotrimazole daily administration for six days. In the second group, 20 women were treated with clotrimazole associated with Unilen Microbio+, a new product containing , melatonin, and GLA-14. Women underwent a check at days 15, 30, and 90. A clinical and cultural examination were performed to establish the effect of the treatments on vaginal flora. In the group treated with Unilen Microbio+, clinical and microbiological cure at 15 and 30 days was observed in 18 women (90%), compared with 16 women (80%) in the group treated only with clotrimazole. The efficacy of the association between clotrimazole and Unilen Microbio+ in these uncomplicated forms was therefore not inferior to the azole treatment alone. Only four women (20%) in the Unilen Microbio+ group presented symptomatic recurrences within the 3 months, compared with eight women (40%) in the clotrimazole-only group. Microscopic wet mount analysis at 1 and 3 months demonstrated a significant increase in lactobacillus count and a reduction in the polymorphonucleate cells in the Unilen Microbio+ group. Unilen Microbio+ supplementation was demonstrated to cure uncomplicated vulvovaginal candidiasis with clotrimazole, reducing recurrence and improving vaginal flora better than clotrimazole treatment alone.
PubMed: 34828601
DOI: 10.3390/healthcare9111555 -
Heliyon Mar 2024Vulvovaginal candidiasis (VVC) is the second most common cause of vaginal infection globally after bacterial vaginosis (BV) and associated with adverse reproductive and... (Review)
Review
Vulvovaginal candidiasis (VVC) is the second most common cause of vaginal infection globally after bacterial vaginosis (BV) and associated with adverse reproductive and obstetric outcomes, including preterm delivery, sexually transmitted infections and pelvic inflammatory disease. Although effective control of VVC is achievable with the use of traditional treatment strategies (i.e., antifungals), the possibility of drug intolerance, treatment failure and recurrence, as well as the appearance of antifungal-resistant species remain critical challenges. Therefore, alternative therapeutic strategies against VVC are urgently required. In recent years, an improved understanding of the dysbiotic vaginal microbiota (VMB) during VVC has prompted the consideration of administering -biotics to restore the balance of the VMB within the context of VVC prevention and treatment. Here, we aim to summarize the current evidence of the anti- effects of probiotics, postbiotics and synbiotics and their potential use as an alternative/complementary therapy against VVC. Additionally, this review discusses advantages and challenges associated with the application of -biotics in VVC to provide guidance for their later use. We also review new developments in VVC therapy, i.e., vaginal microbiota transplantation (VMT) as an emerging live biotherapeutic therapy against VVC and discuss existing shortcomings associated with this nascent field, expecting to stimulate further investigations for introduction of new therapies against VVC.
PubMed: 38463778
DOI: 10.1016/j.heliyon.2024.e27239 -
Biofilm Dec 2023Recurrent vulvovaginal candidiasis (RVVC) is a recalcitrant medical condition that affects many women of reproductive age. The importance of biofilm formation by in...
BACKGROUND
Recurrent vulvovaginal candidiasis (RVVC) is a recalcitrant medical condition that affects many women of reproductive age. The importance of biofilm formation by in RVVC has been recently questioned. This study aimed to elucidate the fundamental growth modes of in the vagina of patients with RVVC or sporadic vulvovaginal candidiasis (VVC) and to assess their roles in the persistence of RVVC.
METHODS
Vaginal tissues were sampled from twelve patients clinically and microbiologically diagnosed as RVVC or VVC at a post-antifungal-treatment and asymptomatic period. High-resolution scanning electron microscopy, fluorescence in situ hybridization in combination with -specific 18S rRNA probes and viable fungal burden were used to qualitatively and quantitatively evaluate growth in the human vagina. The presence of biofilm extracellular polymeric substances was examined using confocal laser scanning microscopy and biopsy sections pre-stained with Concanavalin A. Histopathological analysis was carried out on infected vaginal tissues stained with hematoxylin and eosin. Lastly, the susceptibility of epithelium-associated biofilms to fluconazole at the peak serum concentration was evaluated.
RESULTS
species grew on the vaginal epithelium of RVVC patients as morphologically disparate biofilms including monolayers, microcolonies, and macro-colonies, in addition to sporadic adherent cells. biofilm growth on the vaginal epithelium was associated with mild lymphocytic infiltration of the vaginal mucosa. These epithelium-based biofilms presented an important characteristic contributing to the persistence of RVVC that is the high tolerance to fluconazole.
CONCLUSIONS
In summary, our study provides direct evidence to support the presence of biofilms in RVVC and an important role of biofilm formation in disease persistence.
PubMed: 37941804
DOI: 10.1016/j.bioflm.2023.100162 -
Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.Journal of Women's Health (2002) Feb 2023Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the... (Clinical Trial)
Clinical Trial
Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and species. At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.
Topics: Female; Humans; Antifungal Agents; Candidiasis, Vulvovaginal; Fluconazole; Glycosides
PubMed: 36255448
DOI: 10.1089/jwh.2022.0132