Study of the Dectin-2 receptor signalling in response to Candida albicans in AIRE deficiency human cell

• Grant number: 13/24005-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: May 01, 2014
• End date: April 30, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Antonio Condino Neto
• Grantee: José Antônio Tavares de Albuquerque
• Supervisor: Jordan Scott Orange
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Baylor College of Medicine, United States
• Associated to the scholarship: 11/10736-9 - Study of the Dectin-2 receptor signalling in response to Candida albicans in AIRE deficiency human cell, BP.PD

Abstract

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autoimmune disease caused by mutation in autoimmune regulator gene (AIRE). Patients with AIRE mutation are susceptible to yeast (Candida albicans) infection. To investigate this phenomenon, we previously established that cytoplasmic AIRE could regulate Syk-dependent Dectin-1 pathway and yeast recognition. Dectin-2 receptor, however, directly recognizes hyphae and shares the same Syk-dependent pathway to produce inflammatory cytokines such as TNF-alpha and IL-6. We also found that both receptors are present in the interface between hyphae and macrophages-like cells, which we defined as fungal synapse. Upon hyphae stimulation, AIRE knocked down THP-1 cells or AIRE deficient patient macrophages secreted IL-6 and TNF-alpha in lower levels than the respective control groups. In hyphae activated THP-1 cells, AIRE physically interacted with Dectin-2, Syk, and CARD9. There was also recruitment of AIRE at the fungal-synapse formed between THP-1 cells and hyphae, where AIRE colocalized with Dectin-2 and Syk. Accumulation of Dectin-2 at the fungal synapse reached its peak at 20 minutes. Colocalization between Dectin-1 and Dectin-2 was noted at all time points tested but was highest at 20 min. Dectin-1 accumulation at the synapse was, however, reached saturation at 30 min.In this study, we are going to evaluate the AIRE influence upon Dectin receptors and protein signaling recruitment at the fungal synapse. Another aim of this project is to analyze the role of AIRE protein in early and late events depend on the synapse formation in deficient patients. We believe this study are going to contribute significantly to the advancement of knowledge about the molecular mechanisms involved in susceptibility to candidiasis in APECED. (AU)