Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis
Vasiliki Matzaraki,
Alexandra Beno,
Martin Jaeger,
Mark S. Gresnigt,
Nick Keur,
Collins Boahen,
Cristina Cunha,
Samuel M. Gonçalves,
Luis Leite,
João F. Lacerda,
António Campos, Jr.,
Frank L. van de Veerdonk,
Leo Joosten,
Mihai G. Netea,
Agostinho Carvalho,
Vinod Kumar
Affiliations
Vasiliki Matzaraki
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands; Corresponding author.
Alexandra Beno
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Martin Jaeger
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Mark S. Gresnigt
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knoell-Institute, Jena, Germany
Nick Keur
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Collins Boahen
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Cristina Cunha
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
Samuel M. Gonçalves
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
Luis Leite
Serviço de Transplantação de Medula Óssea (STMO), Instituto Português de Oncologia do Porto, Porto, Portugal
João F. Lacerda
Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
António Campos, Jr.
Serviço de Transplantação de Medula Óssea (STMO), Instituto Português de Oncologia do Porto, Porto, Portugal
Frank L. van de Veerdonk
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Leo Joosten
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands
Mihai G. Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
Agostinho Carvalho
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal
Vinod Kumar
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, 6525 HP, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 9700RB, the Netherlands; Nitte (Deemed to be University), Nitte University Centre for Science Education and Research (NUCSER), Medical Sciences Complex, Deralakatte, Mangalore, 575018, India
Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10−6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.
