Functional and Genomic Architecture of Borrelia burgdorferi-Induced Cytokine Responses in Humans.
Despite the importance of immune variation for the symptoms and outcome of Lyme disease, the factors influencing cytokine production during infection with the causal pathogen Borrelia burgdorferi remain poorly understood. Borrelia infection-induced monocyte- and T cell-derived cytokines were profiled in peripheral blood from two healthy human cohorts of Western Europeans from the Human Functional Genomics Project. Both non-genetic and genetic host factors were found to influence Borrelia-induced cytokine responses. Age strongly impaired IL-22 responses, and genetic studies identified several independent QTLs that impact Borrelia-induced cytokine production. Genetic, transcriptomic, and functional validation studies revealed an important role for HIF-1α-mediated glycolysis in the cytokine response to Borrelia. HIF-1α pathway activation and increase in glycolysis-derived lactate was confirmed in Lyme disease patients. In conclusion, functional genomics approaches reveal the architecture of cytokine production induced by Borrelia infection of human primary leukocytes and suggest a connection between cellular glucose metabolism and Borrelia-induced cytokine production.
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Marije
M
Oosting
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Mariska
M
Kerstholt
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Rob
R
Ter Horst
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, the Netherlands.
Yang
Y
Li
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, the Netherlands; Genomics Coordination Center, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, the Netherlands.
Patrick
P
Deelen
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Sanne
S
Smeekens
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Martin
M
Jaeger
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Ekta
E
Lachmandas
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Hedwig
H
Vrijmoeth
Department of Infectious Diseases, University of Medicine and Pharmacy "Iuliu Hatieganu," 400012 Cluj-Napoca, Romania.
Mihaela
M
Lupse
Department of Infectious Diseases, University of Medicine and Pharmacy "Iuliu Hatieganu," 400012 Cluj-Napoca, Romania.
Mirela
M
Flonta
Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Dartmouth, NH 03755-1404, USA.
Robert A
RA
Cramer
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Bart Jan
BJ
Kullberg
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, the Netherlands.
Vinod
V
Kumar
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Ramnik
R
Xavier
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, the Netherlands.
Cisca
C
Wijmenga
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
Mihai G
MG
Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands. Electronic address: leo.joosten@radboudumc.nl.
Leo A B
LA
Joosten
D000367:Age Factors; D000818:Animals; D001769:Blood; D025065:Borrelia burgdorferi / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D015748:Borrelia burgdorferi Group / Q000235:genetics / Q000472:pathogenicity; D002460:Cell Line; D002470:Cell Survival; D002874:Chromosome Mapping; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood; D004269:DNA, Bacterial; D016680:Genome, Bacterial; D023281:Genomics; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007371:Interferon-gamma; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D007962:Leukocytes; D008193:Lyme Disease / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D059467:Transcriptome; D000097043:Interleukin-22
D016207:Cytokines; D004269:DNA, Bacterial; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D019344:Lactic Acid; D000097043:Interleukin-22; C497442:HIF1A protein, human
Borrelia burgdorferi; HIF-1α; Lyme disease; cytokines; glucose metabolism; host defense