Genome-wide association study in Estonia reveals importance of vaginal epithelium associated genes in case of recurrent vaginitis.

Recurrent vaginitis is a leading reason for visiting a gynaecologist, with bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) being the most common diagnoses. Reasons and mechanisms behind their recurrent nature are poorly understood. We conducted a genome-wide association study (GWAS) to find possible genetic risk factors for recurrent vaginitis using data from a large population-based biobank, the Estonian Biobank. The study included 6870 cases (at least two episodes of vaginitis) and 5945 controls (no vaginitis episodes). GWAS approach included single marker and gene-based analyses, followed by functional annotation of associated variants and candidate gene mapping.In single marker analysis, one statistically significant (P = 7.8 × 10-9) variant rs1036732378 was identified on chromosome 10. The gene-based association analysis identified one gene, KRT6A, that exceeded the recommended significance threshold (P = 2.6 × 10-6). This is a member of the keratin protein family and is expressed during differentiation in epithelial tissues.Functional mapping and annotation of genetic associations by using adjusted significance level identified 22 potential risk loci that may be associated with recurrent vaginitis phenotype. Comparison of our results with previous studies provided nominal support for LBP (associated with immune response to vaginal bacteria) and PRKCH genes (possible role in keratinocyte differentiation and susceptibility to candidiasis).In conclusion, this study is the first highlighting a potential role of the vaginal epithelium in recurrent vaginitis.

Prevalence of Closely Related Candida albicans Species among Patients with Vulvovaginal Candidiasis in Southern Poland Based on the hwp1 Gene Amplification.

Candida albicans remains the most common species isolated from women with vulvovaginal candidiasis. However, closely related species such as Candida africana and Candida dubliniensis may also occur, although they are often misidentified. The aim of the study was to confirm the phenotypic identification of C. albicans and its closely related species isolated from women with genital tract infections by amplification of the hwp1 (hyphal wall protein 1) gene in a PCR assay. We report a detailed molecular identification of C. albicans and its closely related species among 326 patients in the Malopolska region, Poland. Initial phenotypic identifications were confirmed by amplification of the hwp1 gene. Based on molecular analysis, we revealed 307 strains (94.17%) as C. albicans and 17 as C. dubliniensis (5.22%). No strain of C. africana was detected. Two patients h ad co-infection with C. albicans and C. dubliniensis (0.61%). A PCR assay targeting the hwp1 gene was reliable for correctly identifying species among the C. albicans complex.

HLA-DRB1 alleles as predisposing and resisting factor in women suffering from vulvovaginal candidiasis.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a vaginal mucosal infection that usually affects women in their reproductive age. When the signs of VVC persist on a daily basis or last for a long time and repeat at least three times per year, the disease is considered chronic and recurrent. OBJECTIVE: The purpose of this study was to evaluate the frequency of HLA-DRB1 alleles in patients with recurrent vulvovaginal candidiasis (RVVC). STUDY DESIGN: 120 patients with RVVC and 136 age-matched healthy controls underwent low-resolution HLA-DRB typing performed using the polymerase chain reaction-sequence-specific primers (PCR-SSP) technique. RESULTS: In the present work, we studied different genes that encode HLA-DRB (HLA-DRB1 / HLA-DRB3 / HLA-DRB4 / HLA-DRB5) and showed that HLA-DRB1×14, found in 25% of the patients. In the present study, the significant frequency of HLA-DRB1×10 in the control group suggests a resistant role of this allele to RVVC infections CONCLUSIONS: In the HLA-DRB region, the DRB1×14 allele showed a higher frequency in the patients with RVVC than in the controls. Moreover, the higher frequency of DRB1×10 observed in the controls than in the patients with RVVC. These results demonstrate the HLA-DRB1 alleles are in relation with both susceptibility and immunity factors in RVVC infection and possible susceptible role of HLA-DRB1×14.

Candida pathogens induce protective mitochondria-associated type I interferon signalling and a damage-driven response in vaginal epithelial cells.

Vaginal candidiasis is an extremely common disease predominantly caused by four phylogenetically diverse species: Candida albicans; Candida glabrata; Candida parapsilosis; and Candida tropicalis. Using a time course infection model of vaginal epithelial cells and dual RNA sequencing, we show that these species exhibit distinct pathogenicity patterns, which are defined by highly species-specific transcriptional profiles during infection of vaginal epithelial cells. In contrast, host cells exhibit a homogeneous response to all species at the early stages of infection, which is characterized by sublethal mitochondrial signalling inducing a protective type I interferon response. At the later stages, the transcriptional response of the host diverges in a species-dependent manner. This divergence is primarily driven by the extent of epithelial damage elicited by species-specific mechanisms, such as secretion of the toxin candidalysin by C. albicans. Our results uncover a dynamic, biphasic response of vaginal epithelial cells to Candida species, which is characterized by protective mitochondria-associated type I interferon signalling and a species-specific damage-driven response.

Vulvovaginal candidiasis in a murine model of diabetes emphasizing the invasive ability of etiological agents.

Aim: To compare the pathogenesis of vulvovaginal candidiasis by three Candida species in diabetic mice. Materials & methods: Estrogenized and diabetic mice were challenged with C. albicans, C. tropicalis and C. glabrata. Results: Diabetic animals infected with C. albicans and C. tropicalis maintained the highest fungal burden, despite of high levels of proinflammatory cytokines (IL-6 and TNF-α), respectively. For C. glabrata, the results were similar in diabetic and nondiabetic groups. Conclusion:C. tropicalis was as invasive as C. albicans, and both were more effective than C. glabrata. This ability was attributed to filamentation, which may be stimulated by glucose levels from vaginal fluid. In addition, the high burden may be attributed to the apparent immunological inefficiency of the diabetic host.

Differential Expression of Local Immune Response Genes in the Vagina: Implication for the Diagnosis of Vaginal Infections.

Transcription profiles of genes of local immune response were determined in the vagina of women with bacterial vaginosis, aerobic vaginitis, and vulvovaginal candidosis for detection of the most specific immune markers for these vaginal infections. Laboratory diagnosis of the vaginal infections was performed microscopically; the inflammatory reaction in the vagina (leukorrhea) was defined as the presence of >10 white blood cells per field of view. Transcription profiles of IL1b, IL10, IL18, TNFα, TLR4, GATA3, and CD68 were determined using reverse-transcription quantitative real-time PCR. The strongest predictors of aerobic vaginitis were increased levels of IL1b and IL10 mRNA. Bacterial vaginosis was strongly associated with reduced levels of IL18 and GATA3 mRNA. Increased levels of IL1b and TLR4 transcripts showed significant discriminatory power for vulvovaginal candidosis and leukorrhea. The results of this study suggest differential expression of local immune response genes in the vagina of women with different vaginal infections. Detection of specific immune markers in the vagina using reverse-transcriptase PCR could supplement PCR detection of abnormal vaginal microflora for the diagnosis of vaginal infections.

Targeting the Aryl Hydrocarbon Receptor With Indole-3-Aldehyde Protects From Vulvovaginal Candidiasis via the IL-22-IL-18 Cross-Talk.

Vulvovaginal candidiasis (VVC) is a common mucosal infection caused by Candida spp., most frequently by Candida albicans, which may become recurrent and severely impacting the quality of life of susceptible women. Although it is increasingly being recognized that mucosal damage is mediated by an exaggerated inflammatory response, current therapeutic approaches are only based on antifungals that may relieve the symptomatology, but fail to definitely prevent recurrences. The unrestrained activation of the NLRP3 inflammasome with continuous production of IL-1ß and recruitment of neutrophils is recognized as a pathogenic factor in VVC. We have previously shown that IL-22 is required to dampen pathogenic inflammasome activation in VVC via the NLRC4/IL-1Ra axis. However, IL-22 also regulates IL-18, a product of the inflammasome activity that regulates IL-22 expression. Here we describe a cross-regulatory circuit between IL-18 and IL-22 in murine VVC that is therapeutically druggable. We found that IL-18 production was dependent on IL-22 and NLRC4, and that IL-18, in turn, contributes to IL-22 activity. Like in IL-22 deficiency, IL-18 deficiency was associated with an increased susceptibility to VVC and unbalanced Th17/Treg response, suggesting that IL-18 can regulate both the innate and the adaptive responses to the fungus. Administration of the microbial metabolite indole-3-aldehyde, known to stimulate the production of IL-22 via the aryl hydrocarbon receptor (AhR), promoted IL-18 expression and protection against Candida infection. Should low levels of IL-18 be demonstrated in the vaginal fluids of women with recurrent VVC, targeting the AhR/IL-22/IL-18 pathway could be exploited for future therapeutic approaches in VVC. This study suggests that a deeper understanding of the mechanisms regulating inflammasome activity may lead to the identification of novel targets for intervention in VVC.

Vaginal microbiota of asymptomatic bacterial vaginosis and vulvovaginal candidiasis: Are they different from normal microbiota?

Vaginal microbiota contributes in maintaining and protecting the urogenital niche from infections and their sequelae. Despite extensive research, microbiome studies have often ignored asymptomatic bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC). The present study aimed to explore the cultivable vaginal bacterial and mycological communities in women asymptomatic for BV and VVC using multiplex PCR and species-specific PCR. Vaginal swabs collected from 199 participants asymptomatic for urogenital infections, scored by Nugent criteria indicated 73.9% had normal microbiota, 11.6% intermediate and 14.5% BV. The most frequent Lactobacillus species in normal women were L. iners (69.4%), L. crispatus (24.5%), L. reuteri (20.4%). Women with BV colonized L. iners (62.1%); L. rhamnosus (41.4%); L. salivarius (13.7%) and L. reuteri (7.2%). Furthermore, L. crispatus was associated with normal microbiota, whereas L. iners was a frequent member of normal and dysbiotic microbiota. Lactobacillus abundance and species richness reduced in asymptomatic BV. Also L. crispatus, L. fermentum, L. acidophilus and L. delbruckii were absent in these women. L. iners significantly co-existed with other Lactobacillus species, indicating its failure in independently maintaining the healthy vaginal niche. Of 30.4% women detected with Candida, 72.1% constituted non-albicans Candida. Predominance of C. albicans increased from 18.4% in healthy to 60% in women with asymptomatic BV; whereas distribution of BV related bacteria did not vary across the groups. Heterogeneous population of lactobacilli in 80.8% of normal women calls attention towards cumulative effects of these species in safeguarding the vaginal microenvironment. Since the microbiota of asymptomatic BV was different from healthy, screening and management could be encouraged to avoid further complications of infections.

A systems genomics approach identifies SIGLEC15 as a susceptibility factor in recurrent vulvovaginal candidiasis.

Candida vaginitis is a frequent clinical diagnosis with up to 8% of women experiencing recurrent vulvovaginal candidiasis (RVVC) globally. RVVC is characterized by at least three episodes per year. Most patients with RVVC lack known risk factors, suggesting a role for genetic risk factors in this condition. Through integration of genomic approaches and immunological studies in two independent cohorts of patients with RVVC and healthy individuals, we identified genes and cellular processes that contribute to the pathogenesis of RVVC, including cellular morphogenesis and metabolism, and cellular adhesion. We further identified SIGLEC15, a lectin expressed by various immune cells that binds sialic acid-containing structures, as a candidate gene involved in RVVC susceptibility. Candida stimulation induced SIGLEC15 expression in human peripheral blood mononuclear cells (PBMCs) and a polymorphism in the SIGLEC15 gene that was associated with RVVC in the patient cohorts led to an altered cytokine profile after PBMC stimulation. The same polymorphism led to an increase in IL1B and NLRP3 expression after Candida stimulation in HeLa cells in vitro. Last, Siglec15 expression was induced by Candida at the vaginal surface of mice, where in vivo silencing of Siglec15 led to an increase in the fungal burden. Siglec15 silencing was additionally accompanied by an increase in polymorphonuclear leukocytes during the course of infection. Identification of these pathways and cellular processes contributes to a better understanding of RVVC and may open new therapeutic avenues.

SNPs in 3'-UTR region of MBL2 increases susceptibility to recurrent vulvovaginal infections by altering sMBL levels.

Recurrent vulvovaginal infections (RVVI), owing to their adverse health consequences, have become a serious dilemma worldwide. Low serum levels of Mannose-Binding Lectin (sMBL), a main component of innate immunity, was found to be associated with RVVI risk, though complete genetic bases are still elusive. To reveal unrecognised regulatory variants, 3'-UTR region of MBL2 with six putative functional SNPs i.e. rs10824792, rs2120132, rs2120131, rs2165813, rs2099903 and rs2099902 was sequenced and genotyped in the present study for 109 RVVI cases and age matched healthy controls. sMBL levels were measured by enzyme-linked immunosorbent assay. The homozygous CC genotype of rs10824792 polymorphism was found to be conferring risk (OR = 2.94) of developing RVVI. Significantly high frequency of corresponding CC genotype was found in Vulvovaginal Candidiasis (VVC) and Mixed Infections (MI) relative to controls. Significantly insufficient sMBL levels were observed in RVVI and its types (Bacterial Vaginosis, VVC and MI) than controls. sMBL levels varied for rs10824792 SNP as expected from the genetic analyses. Six marker haplotype analyses have shown CTTGCT, the haplotype containing only risk allele of rs10824792, conferred risk of RVVI and its types by lowering sMBL levels. In conclusion, a 3'-UTR SNP i.e. rs10824792 was identified as novel associated genetic marker for contributing low sMBL levels and RVVI risk. Our findings contribute to the novel future research directions for the development of emerging MBL substitution as effectual therapy for RVVI.

IL-9 Integrates the Host-Candida Cross-Talk in Vulvovaginal Candidiasis to Balance Inflammation and Tolerance.

Vulvovaginal candidiasis (VVC) is a common fungal infection caused by Candida albicans. The antifungal therapy represents the standard of care but due to the high costs of treatment and to the inability to prevent recurrences, the development of alternative therapeutic approaches is much-awaited. Recently, we have shown that the pathogenesis of C. albicans in the gut is modulated by IL-9, a pleiotropic cytokine able to promote both inflammation and tolerance during C. albicans infection. Herein, by using a mouse model of VVC, we similarly demonstrated that IL-9 might exert a dual role in VVC by contributing to inflammation during the initial immune activation and promoting resolution thereafter. Specifically, IL-9 has a pro-inflammatory activity at the onset of VVC by promoting NLRP3 inflammasome activity and mucosal mast cells expansion but a tolerogenic role in the resolution phase by promoting IL-1Ra production and connective tissue mast cells activation. We further show that a timely IL-9 neutralization at the onset of the inflammatory response ameliorated symptoms and vaginal pathology. Given that vaginal fluids from patients with recurrent VVC had higher levels of IL-9, these findings, by providing novel insights into the pathogenesis of VVC, may pave the way for alternative therapeutic strategies based on IL-9 neutralization.

Protective Effects of cis-2-Dodecenoic Acid in an Experimental Mouse Model of Vaginal Candidiasis.

OBJECTIVE: To evaluate the efficacy of cis-2-dodecenoic acid (BDSF) in the treatment and prevention of vaginal candidiasis in vivo. METHODS: The activities of different concentrations of BDSF against the virulence factors of Candida albicans (C. albicans) were determined in vitro. An experimental mouse model of Candida vaginitis was treated with 250 µmol/L BDSF. Treatment efficiency was evaluated in accordance with vaginal fungal burden and inflammation symptoms. RESULTS: In vitro experiments indicated that BDSF attenuated the adhesion and damage of C. albicans to epithelial cells by decreasing phospholipase secretion and blocking filament formation. Treatment with 30 µmol/L BDSF reduced the adhesion and damage of C. albicans to epithelial cells by 36.9% and 42.3%, respectively. Treatment with 200 µmol/L BDSF completely inhibited phospholipase activity. In vivo mouse experiments demonstrated that BDSF could effectively eliminate vaginal infection and relieve inflammatory symptoms. Four days of treatment with 250 µmol/L BDSF reduced vaginal fungal loads by 6-fold and depressed inflammation. Moreover, BDSF treatment decreased the expression levels of the inflammatory chemokine-associated genes MCP-1 and IGFBP3 by 2.5- and 2-fold, respectively. CONCLUSION: BDSF is a novel alternative drug that can efficiently control vaginal candidiasis by inhibiting the virulence factors of C. albicans.

Mannose-Binding Lectin Gene Polymorphism and Its Association with Susceptibility to Recurrent Vulvovaginal Candidiasis.

Recurrent vulvovaginal candidiasis (RVVC) is a common illness influencing childbearing women worldwide. Most women suffering from RVVC develop infection without specified risk factors. Mannose-binding lectin (MBL) is an important component of innate immune defense against Candida infection. Innate immunity gene mutations and polymorphisms have been suggested to play a role in susceptibility to RVVC. This study aimed to investigate the association between MBL 2 gene exon 1 codon 54 polymorphism and susceptibility to RVVC in childbearing women. Whole blood and serum samples were obtained from 59 RVVC cases and 59 controls. MBL serum level was measured by enzyme-linked immune-sorbent assay (ELISA). MBL2 exon 1 codon 54 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). It was shown that MBL serum level was nonsignificantly different between RVVC cases and controls. The risk of RVVC was 3 times higher in those carrying MBL2 exon 1 codon 54 variant allele (B). It could be concluded that the carrying of MBL2 exon 1 codon 54 variant allele (B) was shown to be a risk factor for RVVC in childbearing women.

The Case for an Expanded Concept of Trained Immunity.

Trained immunity was originally proposed as a program of innate immunity memory by innate immunity cells of hematopoietic origin such as the monocytes/macrophages and the NK cells. Here I discuss some old and new data justifying this program and some specific, still unanswered, questions it raises regarding the model fungus Candida albicans and the chronic, inflammatory vulvovaginal disease it causes. Building upon this well-established program, the recent reports that epithelial cells of mammals can also acquire memory from previous stimulations, and the apparent intrinsic ability of many living cells from bacteria to mammals to learn from experience, I suggest an expansion of the concept of trained immunity to include all cells of different lineages with the potential of memorizing previous microbial encounters. This expansion would better fit the complexity of innate immunity and the role it plays in infectious and inflammatory diseases.

A Comprehensive in Silico Analysis of Regulatory SNPs of Human CLEC7A Gene and Its Validation as Genotypic and Phenotypic Disease Marker in Recurrent Vulvovaginal Infections.

Recurrent Vulvovaginal infections (RVVI) are the commonly reported microbiological syndrome affecting millions of women globally. Various molecules of innate immune system are instrumental in clearance of these microbial pathogens, thus suggested as one of the most important contributing factor in determining the disease outcome. Dendritic cell-associated C-type lectin-1 (Dectin-1) is an important molecule of innate immunity that is primarily known for its role in antifungal defenses. However, role of dectin-1 in recognition of other pathogens is also documented. The intracellular expression of dectin-1 was shown to be up-regulated by Mannose Binding Lectin (MBL)-mediated opsonophagocytosis of pathogens. Dectin-1 is encoded by CLEC7A, postulated to be a candidate gene in modulating risk of developing RVVI. In this study, we identified CLEC7A causal variants using in silico analysis. To assess their impact on susceptibility to RVVI, these causal variants along with serum dectin-1 levels (sDectin-1) were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Enzyme Linked Immnosorbent Assay (ELISA) respectively, under a case-control design. Furthermore, effect of these polymorphisms was also assessed on sMBL levels. In silico analysis revealed 9 putative functional conserved SNPs of CLEC7A. Association analysis revealed a significantly lower risk of developing RVVI and its types in carriers of CLEC7A rs3901533 G allele and its homozygous genotypes (p < 0.05). The heterozygous genotype was associated with significant protection against RVVI (p = 0.004). Haplotypes GGG and GTA showed significant protection against RVVI (p < 0.0001; p = 0.0003), Bacterial Vaginosis (p = 0.03; p = 0.002), Vulvovaginal Candidiasis (p = 0.03; p = 0.01) and Mixed Infections (p = 0.007; p = 0.04). Mean sDectin-1 levels were significantly high in RVVI and its types compared to controls (p < 0.05). Further, genotype-phenotype stratification showed significant differences within/between cases groups and controls. The CLEC7A rs3901533 polymorphism was also found to be associated with sMBL levels. The present study contributed novel insights into the role of dectin-1 in RVVI. CLEC7A rs3901533 polymorphism and high sDectin-1 levels along with low sMBL levels were found to be associated with RVVI susceptibility. Thus, screening of women with RVVI for these novel associations may lead to better diagnosis and treatment. Also genotyping method used in this study constitutes a simple and reliable assay, which can be confidently, used as a cheaper alternative for genotyping these variants in clinical settings. Finally, new restorative markers for other infectious diseases might be found by exploring nine functionally identified CLEC7A SNPs.

Knockout of autophagy gene, ATG5 in mice vaginal cells abrogates cytokine response and pathogen clearance during vaginal infection of Candida albicans.

The female reproductive tract (FRT) presents a unique challenge to the mucosal immune system as it needs to monitor constantly for the presence of opportunistic pathogens amidst its commensal flora. During infection, autophagy plays a critical role in pathogen clearance, presentation of antigens and production of pro-inflammatory cytokines. However, no information is available that describes the role of autophagy in mouse vaginal infection of Candida albicans. The objective of our study is to evaluate the effect of autophagy gene, ATG5 knockout in vaginal cells in response to vaginal C. albicans infection. Mice having knockout of ATG5 in the vaginal cells (PR-ATG5-KO mice) were infected intra-vaginally with the yeast form of Candida albicans. Vaginal lavages were collected once in a week until the infection was cleared. We detected the expression of autophagy marker genes (LC3, ATG5 and LAMP1) in the vaginal cells. We determined the levels of various cytokines (IL-1α, IL-1ß, IL-6, IL-10, IL-17A, IL-22, IL-23p19, TNF-α and G-CSF) involved in anti-candida response. The levels of cytokines in the vaginal lavages were quantified using Aimplex Premixed analyte kit. The vaginal lavages were checked for polymorphonuclear leucocytes (PMNLs) infiltration. The candida clearance rate from the vaginal lumen was determined by Colony Forming Units (CFUs) assay. The results revealed that PR-ATG5-KO mice failed to induce the expression of LC3, ATG5 and LAMP1 indicating an impaired autophagy pathway. The levels of all the cytokines (except IL-10) in C. albicans infected PR-ATG5-KO mice were significantly reduced as compared to the wild type infected C57BL/6 mice. The number of PMNLs infiltrated into the vaginal lavages of infected PR-ATG5-KO mice was reduced. The clearance of C. albicans from the vaginal lumen was also considerably delayed in PR-ATG5-KO mice. In conclusion, the results revealed that impaired autophagy in vaginal cells influences host response during vaginal infection of C. albicans by affecting anti-Candida cytokine levels in the vaginal lavage resulting in reduction of pathogen clearance rate.

High glucose-mediated overexpression of ICAM-1 in human vaginal epithelial cells increases adhesion of Candida albicans.

To investigate the involvement of ICAM-1 in the adhesion of Candida to the genitourinary epithelial cells in high glucose, we examined the adhesion of Candida albicans or Candida glabrata to human vaginal epithelial cells (VK2/E6E7) or human vulvovaginal epidermal cells (A431). These cells were cultured in 100, 500 or 3000 mg/dL glucose for three days and inoculated with Candida for 60 minutes. Followed by, adhering of Candida to the cells, which were counted. While the adhesion of Candida albicans to VK2/E6E7 significantly increased in the high glucose, A431 did not. We next examined the expression of ICAM-1 as a ligand on the epithelial cells. ICAM-1 expression was increased in VK2/E6E7 cultured in the high glucose; however, the expression level in A431 was not high compared with VK2/E6E7. This data suggested that ICAM-1 functions as one of ligands in the adhesion of Candida albicans to the vaginal epithelial cells in a high glucose environment. Impact statement What is already known on the subject: Candida's complement receptor is involved in the adhesion to epithelial cells. The expression of this receptor has been reported to increase as glucose concentration increases. This is considered as a contributing factor to the high risk for vulvovaginal candidiasis (VVC) in diabetes. On the host side, diabetic patients have a factor that facilitates adhesion of Candida to epithelial cells. This factor has been unknown until recently. What the results of this study add: In this study, we used a vaginal epithelial cell line and showed that the adhesion of C. albicans to cells increased at higher glucose concentrations. At the same time, ICAM-1 expression of cells also increased. Thereby, it is suggested that the expression of ICAM-1 in vaginal epithelial cells is increased by glucose such as urinary sugar in diabetic patients and is a condition for facilitating adhesion of Candida. What the implications are of these findings for clinical practice and/or further research: We expect not only host immune dysfunction but also alteration in epithelial cells will be focussed on as a cause of VVC in diabetic patients.

Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections.

Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.

Contribution of TLR2 pathway in the pathogenesis of vulvovaginal candidiasis.

Candida albicans is the prevalent etiological agent in acute vulvovaginal infection and the most severe chronic condition known as recurrent vulvovaginal candidiasis (VVC). A critical role of local innate immunity in defense and pathogenesis of vaginal infection by Candida is proposed. The fungal recognition by the innate immune receptor is an essential step for the induction of local responses including cytokines and antimicrobial peptides (AMPs) production for host protection. Using TLR2-deficient mice, we characterized the early innate immune response during VVC. Intravaginal challenge of TLR2-/- mice with C. albicans demonstrated that in response to the initial massive penetration, a strong local inflammatory reaction with recruitment of polymorphonuclear neutrophils was developed. Both interleukin 1ß (IL1ß)-regarded as the hallmark of VVC immunopathogenesis-and IL6 were increased in vaginal lavage. Murine beta defensin 1 (mBD1), a constitutive AMP with fungicidal and chemotactic activity, was significantly upregulated in wild type (WT) animals in response to infection. Interestingly, in the absence of TLR2 recognition, levels of mBD1 RNA more than twice higher than those in WT infected animals were observed. Interestingly, our results demonstrate that TLR2 signaling is important to control the fungal burden in the vaginal tract. These finding provide new evidence about the role of this innate receptor during VVC.

[Vulvovaginal candidiasis: An old disease with new challenges]. / Candidiasis vulvovaginal: una antigua enfermedad con nuevos desafíos.

Vulvovaginal candidiasis is an old disease that, even in a modern world, continues to have a high incidence. Despite the therapeutic advances, treatments are not always effective, and our understanding of the pathogenesis of this fungal infection is still incomplete. A discussion is presented in this article on the most significant developments related to the fungal virulence factors, the role of the immunological mechanisms involved in the vaginal protection, and the genetic alterations that confer susceptibility to the recurrent form of this mycosis. Current treatments, the use of new agents with antifungal activity, as well as the development of strategies, such as vaccination, are approached in the context of the complex scenario that governs the interactions between Candida and its host.