scholarly journals Candida albicans Adhesion to and Invasion and Damage of Vaginal Epithelial Cells: Stage-Specific Inhibition by Clotrimazole and Bifonazole

2011 ◽  
Vol 55 (9) ◽  
pp. 4436-4439 ◽  
Author(s):  
Betty Wächtler ◽  
Duncan Wilson ◽  
Bernhard Hube
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Antifungal Agents ◽  
Vaginal Epithelium ◽  
Specific Inhibition ◽  
Content Type ◽  
Vaginal Epithelial Cells ◽  
Specific Activities ◽  
Low Levels ◽  
Adhesion And Invasion

ABSTRACTClotrimazole and bifonazole are highly effective antifungal agents against mucosalCandida albicansinfections. Here we examined the effects of low levels of clotrimazole and bifonazole on the ability ofC. albicansto adhere, invade, and damage vaginal epithelial cells. Although adhesion and invasion were not affected, damage was greatly reduced upon azole treatment. This clearly indicates that low levels of azoles influence specific activities ofC. albicansduring distinct stages of vaginal epithelium infections.

scholarly journals Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Eva Pericolini ◽  
Elena Gabrielli ◽  
Mario Amacker ◽  
Lydia Kasper ◽  
Elena Roselletti ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Common Disease ◽  
Content Type ◽  
Neutrophil Influx ◽  
Caspase 1 ◽  
Vaginal Epithelial Cells ◽  
Pepstatin A ◽  
Aspartyl Proteinases

ABSTRACTVaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungusCandida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits ofC. albicansthat have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candidavaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated byC. albicansintravaginal injection, and a mutant strain lackingSAP1,SAP2, andSAP3was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteinsin vivoand can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells toC. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis.IMPORTANCECandidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- andC. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti-Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response.

scholarly journals Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis

2013 ◽  
Vol 82 (2) ◽  
pp. 783-792 ◽  
Author(s):  
Junko Yano ◽  
Glen E. Palmer ◽  
Karen E. Eberle ◽  
Brian M. Peters ◽  
Thomas Vogl ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Candida Albicans ◽  
Epithelial Cells ◽  
Biologically Active ◽  
Polymorphonuclear Neutrophil ◽  
Vaginal Candidiasis ◽  
Content Type ◽  
Vaginal Epithelial Cells

ABSTRACTVulvovaginal candidiasis (VVC), caused byCandida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response toC. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previousin vitrodata and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluatedin vitroorin vivoin the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression andC. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reportedin vitrodata, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxisin vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9−/−mice, had no effect on the PMN responsein vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction inC. albicans-induced S100A8/S100A9 mRNAsin vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response toC. albicansinvolves PRRs in addition to SIGNR1 and TLR4, or other induction pathways.

scholarly journals Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

2015 ◽  
Vol 83 (7) ◽  
pp. 2614-2626 ◽  
Author(s):  
Rohitashw Kumar ◽  
Darpan Saraswat ◽  
Swetha Tati ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Oral Candidiasis ◽  
Oral Microbiome ◽  
Proteinase Activity ◽  
Adhesion Properties ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

scholarly journals Evaluation of Immunostimulatory Activities of Synthetic Mannose-Containing Structures Mimicking the β-(1→2)-Linked Cell Wall Mannans of Candida albicans

2012 ◽  
Vol 19 (11) ◽  
pp. 1889-1893 ◽  
Author(s):  
Kaarina Ranta ◽  
Kaisa Nieminen ◽  
Filip S. Ekholm ◽  
Moniká Poláková ◽  
Mattias U. Roslund ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Mouse Macrophages ◽  
Ifn Γ ◽  
Low Levels ◽  
Necrosis Factor

ABSTRACTImmunostimulatory properties of synthetic structures mimicking the β-(1→2)-linked mannans ofCandida albicanswere evaluatedin vitro. Contrary to earlier observations, tumor necrosis factor (TNF) production was not detected after stimulation with mannotetraose in mouse macrophages. Divalent disaccharide 1,4-bis(α-d-mannopyranosyloxy)butane induced TNF and some molecules induced low levels of gamma interferon (IFN-γ) in human peripheral blood mononuclear cells (PBMC).

scholarly journals The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans

2016 ◽  
Vol 60 (10) ◽  
pp. 6369-6373 ◽  
Author(s):  
Guan-Yu Lin ◽  
Hsueh-Fen Chen ◽  
Yao-Peng Xue ◽  
Ying-Chieh Yeh ◽  
Chia-Lu Chen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Antimicrobial Peptides ◽  
Antifungal Agents ◽  
Low Ph ◽  
Planktonic Cells ◽  
Content Type ◽  
Peptide Derivatives ◽  
Helix Conformation ◽  
Α Helix

ABSTRACTTwo antimicrobial P-113 peptide derivatives, P-113Du and P-113Tri, were investigated in this study. Notably, P-113Du and P-113Tri contained significant fractions of α-helix conformation and were less sensitive to high salt and low pH than P-113. Moreover, compared to P-113, these peptides exhibited increased antifungal activity against planktonic cells, biofilm cells, and clinical isolates ofCandida albicansand non-albicans Candidaspp. These results suggest that P-113Du and P-113Tri are promising candidates for development as novel antifungal agents.

EFFECTS OF POSTPUBERTAL OESTROGEN INJECTIONS ON MITOTIC ACTIVITY OF VAGINAL AND UTERINE EPITHELIAL CELLS IN MICE TREATED NEONATALLY WITH OESTROGEN

1975 ◽  
Vol 64 (1) ◽  
pp. 133-140 ◽  
Author(s):  
TAKAO MORI
Keyword(s):  
Epithelial Cells ◽  
Generation Time ◽  
Mitotic Rate ◽  
Cell Number ◽  
Mixed Population ◽  
Vaginal Epithelium ◽  
Uterine Epithelium ◽  
Uterine Epithelial Cells ◽  
Ovariectomized Mice ◽  
Vaginal Epithelial Cells

SUMMARY Cell cycles of vaginal and uterine epithelial cells were studied using [3H]thymidine autoradiography in adult ovariectomized mice given oestrogen injections neonatally. The mice were in a 'persistent-oestrous' state, showing ovary-independent, continued proliferation and cornification of the vaginal epithelium. The duration of different stages of the cell cycle could not be assessed in such mice, since the percentage of labelled mitoses failed to rise to 100%. In neonatally oestrogenized, adult mice the vaginal epithelium appeared to contain a mixed population of cells. After an oestrogen injection, almost all mitoses of vaginal epithelial cells became labelled, with a generation time of about 17 h. By contrast, the generation time was about 15 h in vaginal epithelial cells of ovariectomized 'normal' mice injected with oestrogen when adult. The uterine epithelium of neonatally oestrogenized, ovariectomized mice also consisted of a mixed population of cells. A single oestrogen injection produced an increase in both the mitotic rate and cell number in the vaginal and uterine epithelium of ovariectomized 'normal' adults but not in neonatally oestrogenized, ovariectomized adults. These studies show that in mice given oestrogen neonatally, uterine and vaginal epithelial cells were not responsive to oestrogen or at least less sensitive to oestrogen than ovariectomized 'normal' controls.

scholarly journals Putative Adhesion Factors in Vaginal Lactobacillus gasseri DSM 14869: Functional Characterization

2019 ◽  
Vol 85 (19) ◽  
Author(s):  
Zhu Zeng ◽  
Fanglei Zuo ◽  
Harold Marcotte
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Bacterial Vaginosis ◽  
Hela Cells ◽  
Molecular Mechanisms ◽  
Wild Type ◽  
Content Type ◽  
Lactobacillus Gasseri ◽  
Vaginal Epithelial Cells ◽  
Knockout Mutants

ABSTRACT Lactobacilli play an important role in the maintenance of a healthy vaginal microbiota, and some select species are widely used as probiotics. Vaginal isolates of Lactobacillus gasseri DSM 14869 and Lactobacillus rhamnosus DSM 14870 were previously selected to develop the probiotic EcoVag capsules and showed therapeutic effects in women with bacterial vaginosis (BV). However, the molecular mechanisms involved in their probiotic activity are largely unknown. In this study, we identified three cell surface molecules in L. gasseri DSM 14869 that promote adhesion to vaginal epithelial cells (VEC) by constructing dedicated knockout mutants, including exopolysaccharides (EPSs), a protein containing MucBP-like domains (N506_1778), and a putative novel adhesin (N506_1709) with rib/alpha-like domain repeats. EPS knockout mutants revealed 20-fold and 14-fold increases in adhesion to Caco-2 and HeLa cells, respectively, compared with wild type, while the adhesion to VEC was reduced 30% by the mutation, suggesting that EPSs might mediate tissue tropism for vaginal cells. A significant decrease in adhesion to Caco-2 cells, HeLa cells, and VEC was observed in the N506_1778 knockout mutant. The N506_1709 mutant showed no significant difference for the adhesion to Caco-2 and HeLa cells compared with wild type (WT); in contrast, the adhesion to VEC revealed a significant decrease (42%), suggesting that N506_1709 might mediate specific binding to stratified squamous epithelial cells, and this putative novel adhesin was annotated as Lactobacillus vaginal epithelium adhesin (LVEA). Thus, we have discovered an important role for EPSs and a novel adhesin, LVEA, in the adhesive capacity of a vaginal probiotic Lactobacillus strain. IMPORTANCE Lactobacilli are known to contribute to the maintenance of a healthy vaginal microbiota and some are selected as probiotics for the prevention or treatment of urogenital diseases, such as bacterial vaginosis. However, the molecular mechanisms for these health-promoting effects are not fully understood. Here, we functionally identified three cell surface factors of a Lactobacillus gasseri strain potentially involved in its adhesion to vaginal epithelial cells, including exopolysaccharides (EPSs) and two sortase-dependent proteins (N506_1778 and N506_1709). We could demonstrate the tissue-specific adhesion of EPSs to vaginal cells and that N506_1709 might be a novel adhesin specifically mediating bacterial binding to stratified squamous epithelial cells. The results provide important new information on the molecular mechanisms of vaginal Lactobacillus spp. adhesion.

scholarly journals Impact of Hydroxychloroquine-Loaded Polyurethane Intravaginal Rings on Lactobacilli

2015 ◽  
Vol 59 (12) ◽  
pp. 7680-7686 ◽  
Author(s):  
Yannick Leandre Traore ◽  
Yufei Chen ◽  
Anne-Marie Bernier ◽  
Emmanuel A. Ho
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Female Genital Tract ◽  
Vaginal Epithelial Cell ◽  
Content Type ◽  
Cell Monolayers ◽  
Intravaginal Rings ◽  
Vaginal Epithelial Cells ◽  
Epithelial Cell Monolayers ◽  
The Impact

ABSTRACTThe use of polymeric devices for controlled sustained delivery of drugs is a promising approach for the prevention of HIV-1 infection. Unfortunately, certain microbicides, when topically applied vaginally, may be cytotoxic to vaginal epithelial cells and the protective microflora present within the female genital tract. In this study, we evaluated the impact of hydroxychloroquine (HCQ)-loaded, reservoir-type, polyurethane intravaginal rings (IVRs) on the growth ofLactobacillus crispatusandLactobacillus jenseniiand on the viability of vaginal and ectocervical epithelial cells. The IVRs were fabricated using hot-melt injection molding and were capable of providing controlled release of HCQ for 24 days, with mean daily release rates of 17.01 ± 3.6 μg/ml in sodium acetate buffer (pH 4) and 29.45 ± 4.84 μg/ml in MRS broth (pH 6.2). Drug-free IVRs and the released HCQ had no significant effects on bacterial growth or the viability of vaginal or ectocervical epithelial cells. Furthermore, there was no significant impact on the integrity of vaginal epithelial cell monolayers, in comparison with controls, as measured by transepithelial electrical resistance. Overall, this is the first study to evaluate the effects of HCQ-loaded IVRs on the growth of vaginal flora and the integrity of vaginal epithelial cell monolayers.

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