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Sci Transl Med. 2019 Jun 12;11(496). pii: eaar3558. doi: 10.1126/scitranslmed.aar3558.

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

Author information

1
Department of Internal Medicine and Radboud Centre for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, 6525GA, Netherlands.
2
Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen Medical Center (Radboudumc), Nijmegen, 6525GA, Netherlands.
3
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, 80078, Italy.
4
Department of Human Genetics, Donders Center for Neuroscience, Radboud University Medical Center, Nijmegen, 6525HR, Netherlands.
5
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, Perugia, 06123, Italy.
6
University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9713GZ, Netherlands.
7
Department of Radiation Oncology, Radiotherapy & OncoImmunology Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 32, Nijmegen, 6525GA, Netherlands.
8
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Beutenbergstraße 11a, Jena, 07745, Germany.
9
College of Computer, Qinghai Normal University, 810008 Xining, China.
10
BGI-Shenzhen, Shenzhen 518083, China.
11
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6229HX, Netherlands.
12
Infectious Diseases, Wayne State University School of Medicine, Detroit, MI 48201, USA.
13
Department of Internal Medicine and Radboud Centre for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, 6525GA, Netherlands. mihai.netea@radboudumc.nl.
14
Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, 200349.

Abstract

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.

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