Abstract

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource.

Common genetic variants can affect an individual’s immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.

Details

Title
A comprehensive genetic map of cytokine responses in Lyme borreliosis
Author
Botey-Bataller, Javier 1   VIAFID ORCID Logo  ; Vrijmoeth, Hedwig D. 2   VIAFID ORCID Logo  ; Ursinus, Jeanine 3 ; Kullberg, Bart-Jan 4 ; van den Wijngaard, Cees C. 5 ; ter Hofstede, Hadewych 4 ; Alaswad, Ahmed 6 ; Gupta, Manoj K. 7 ; Roesner, Lennart M. 8   VIAFID ORCID Logo  ; Huehn, Jochen 9   VIAFID ORCID Logo  ; Werfel, Thomas 8 ; Schulz, Thomas F. 10   VIAFID ORCID Logo  ; Xu, Cheng-Jian 1 ; Netea, Mihai G. 11   VIAFID ORCID Logo  ; Hovius, Joppe W. 12 ; Joosten, Leo A. B. 13   VIAFID ORCID Logo  ; Li, Yang 14   VIAFID ORCID Logo 

1  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Hannover, Germany (GRID:grid.512472.7); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany (GRID:grid.452370.7) (ISNI:0000 0004 0408 1805) 
2  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Center for Infectious Disease Control, National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands (GRID:grid.31147.30) (ISNI:0000 0001 2208 0118) 
3  Center for Infectious Disease Control, National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands (GRID:grid.31147.30) (ISNI:0000 0001 2208 0118); Division of Infectious Diseases & Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Amsterdam, the Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
4  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
5  Center for Infectious Disease Control, National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands (GRID:grid.31147.30) (ISNI:0000 0001 2208 0118) 
6  a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Hannover, Germany (GRID:grid.512472.7); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany (GRID:grid.452370.7) (ISNI:0000 0004 0408 1805) 
7  a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Hannover, Germany (GRID:grid.512472.7); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany (GRID:grid.452370.7) (ISNI:0000 0004 0408 1805); Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877) 
8  Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877); Hannover Medical School, Department of Dermatology and Allergy, Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877) 
9  Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877); Helmholtz Centre for Infection Research, Department of Experimental Immunology, Braunschweig, Germany (GRID:grid.7490.a) (ISNI:0000 0001 2238 295X) 
10  Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877); Hannover Medical School, Institute of Virology, Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877) 
11  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); University of Bonn, Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
12  Division of Infectious Diseases & Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Department of Internal Medicine, Amsterdam, the Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
13  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Iuliu Hatieganu University of Medicine and Pharmacy, Department of Medical Genetics, Cluj-Napoca, Romania (GRID:grid.411040.0) (ISNI:0000 0004 0571 5814) 
14  Radboud university medical center, Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, Hannover, Germany (GRID:grid.512472.7); a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany (GRID:grid.452370.7) (ISNI:0000 0004 0408 1805); Hannover Medical School, Cluster of Excellence RESIST (EXC 2155), Hannover, Germany (GRID:grid.10423.34) (ISNI:0000 0000 9529 9877) 
Pages
3795
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-47505-z
ProQuest document ID
3051760490
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.