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Immune-Related Gene Implicated in Chronic Candida Yeast Infection Risk

NEW YORK (GenomeWeb) – Women carrying a specific version of the SIGLEC15 gene appear to be particularly prone to repeated vaginal infections involving Candida fungi, according to new research reported online today in Science Translational Medicine.

Investigators at centers in the Netherlands, Italy, and beyond relied on a so-called 'systems genomics' approach to search for genetic features that coincided with recurrent vulvovaginal candidiasis — defined as three or more bouts of Candida albicans yeast infection each year — in hundreds of European women with or without the condition. Results of their combined exome sequencing, quantitative trait locus, and association analyses led to the sialic acid-binding, immunoglobulin-like lectin-coding SIGLEC15 as a candidate gene for recurrent vulvovaginal Candida infection susceptibility.

That gene is expressed by several immune cell types, the team noted, and found at higher-than-usual levels in Candida-exposed peripheral blood mononuclear cells and at the vaginal surface in mouse models of Candida infection. When the authors introduced the recurrent vulvovaginal candidiasis risk SNP into the HeLa cell line, meanwhile, they found that this version of the SIGLEC15 gene corresponded with enhanced expression of T cell cytokine-related genes.

"[A] complementary approach using genetic and functional immune data identified a number of susceptibility genes in [the] immune system, among them SIGLEC15, a recognition factor for C. albicans," senior and corresponding author Mihai Netea, an immunology researcher affiliated with Radboud University and Craiova University, and his colleagues wrote. "Both in vitro and in vivo validation studies supported an important role of SIGLEC15 for [recurrent vulvovaginal candidiasis] and also suggested that immune hyper-responsiveness of individuals bearing the risk … variants is responsible for the clinical symptoms."

Although Candida often turns up as a harmless, commensal organism in healthy individuals, the team explained, the fungus can prompt serious, systemic infections in immunocompromised individuals and contributes to even more common non-invasive mucosal infections. In particular, the authors noted that a significant proportion of women go through several vulvovaginal Candida yeast infections annually, including many who lack non-genetic risk factors such as prolonged antibiotic or oral contraceptive use.

"A limited number of studies have examined a series of genetic polymorphisms in different pathways that contribute to increased susceptibility to [recurrent vulvovaginal candidiasis]," the authors wrote. "However, these studies were based on only a few previously identified genes, and no comprehensive assessment of the host genetic component in [recurrent vulvovaginal candidiasis] has been performed so far."

Using Agilent SureSelect enrichment kits and Illumina instruments, collaborators at BGI did exome sequencing on women from two European cohorts: 80 cases and 77 controls from southern Europe and, from northern Europe, 75 affected women and 95 unaffected controls.

The researchers also turned to in vitro methods such as flow cytometry, enzyme-linked immunosorbent assays, or gene silencing to track cytokine responses to Candida in 73 of the control individuals, uncovering fungus-related shifts that were subsequently verified in 50 more participants. They fed those findings into a Candida-related cytokine QTL analysis, which was considered alongside exome sequences to identify SNPs, genes, and pathways contributing to frequent Candida infections.

Along with general shifts in pathways related to cell morphogenesis, cell adhesion, and metabolism, for example, the team identified a recurrent infection-related variant called rs2919643 in SIGLEC15 that was evaluated in more detail in peripheral mononuclear blood cell, human cell line, and mouse experiments.

For example, the researchers reported that SIGLEC15 expression jumped in response to Candida in vaginal surface samples from exposed mice, while the fungal burden and polymorphonuclear leukocyte content shot up when the gene was silenced in human blood cells or mice. 

The authors noted that their current findings need to be validated in still other, independent cohorts, and called for further research into the possibility of developing improved diagnostic strategies, targeted treatments, and other therapeutic improvements for women with recurrent vulvovaginal candidiasis.

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