Genome-Wide Association Study Reveals CLEC7A and PROM1 as Potential Regulators of Paracoccidioides brasiliensis-Induction of Cytokine Production in Peripheral Blood Mononuclear Cells

Ana Marina B de Figueiredo; Jéssica Cristina Dos Santos; Brenda Kischkel; Edwin Ardiansyah; Marije Oosting; Grazzielle Guimarães Matos; Iara Barreto Neves Oliveira; Frank van de Veerdonk; Mihai G Netea; Célia Maria de Almeida Soares; Fátima Ribeiro-Dias; Leo A B Joosten

doi:10.3390/jof9040428

Genome-Wide Association Study Reveals CLEC7A and PROM1 as Potential Regulators of Paracoccidioides brasiliensis-Induction of Cytokine Production in Peripheral Blood Mononuclear Cells

J Fungi (Basel). 2023 Mar 30;9(4):428. doi: 10.3390/jof9040428.

Affiliations

¹ Laboratório de Imunidade Natural (LIN), Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia 74605-050, Goiás, Brazil.
² Department of Internal Medicine, Radboud Institute for Molecular Sciences (RILMS) and Radboud Center of Infectious Diseases (RCI), Radboud University Medical Center, 6524 Nijmegen, The Netherlands.
³ Departamento de Microbiologia, Instituto de Ciência Biomédicas, Universidade de São Paulo, São Paulo 05508-000, São Paulo, Brazil.
⁴ Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia 74690-900, Goiás, Brazil.

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi of the genus Paracoccidioides and the different clinical forms of the disease are associated with the host immune responses. Quantitative trait loci mapping analysis was performed to assess genetic variants associated with mononuclear-cells-derived cytokines induced by P. brasiliensis on 158 individuals. We identified the rs11053595 SNP, which is present in the CLEC7A gene (encodes the Dectin-1 receptor) and the rs62290169 SNP located in the PROM1 gene (encodes CD133) associated with the production of IL-1β and IL-22, respectively. Functionally, the blockade of the dectin-1 receptor abolished the IL-1β production in P. brasiliensis-stimulated PBMCs. Moreover, the rs62290169-GG genotype was associated with higher frequency of CD38⁺ Th1 cells in PBMCs cultured with P. brasiliensis yeasts. Therefore, our research indicates that the CLEC7A and PROM1 genes are important for the cytokine response induced by P. brasiliensis and may influence the Paracoccidioidomycosis disease outcome.

Keywords: CD38; CLEC7A; GWAS; PROM1; Paracoccidioidomycosis; genetic polymorphism.

Grants and funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES)–Finance Code 001; A.M.B.F. is a CAPES fellow. PRONEM (2017/10267000516) and National Institute of Science and Technology of the strategies in host-pathogen interaction (INCT-IPH; 465771/2014-9) grants are from Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG), Brazil; F.R-D and C.M.A.S. are fellow researchers of National Council for Scientific and Technological Development (CNPq), Brazil.