A comprehensive genetic map of cytokine responses in Lyme borreliosis

Javier Botey-Bataller; Hedwig D Vrijmoeth; Jeanine Ursinus; Bart-Jan Kullberg; Cees C van den Wijngaard; Hadewych Ter Hofstede; Ahmed Alaswad; Manoj K Gupta; Lennart M Roesner; Jochen Huehn; Thomas Werfel; Thomas F Schulz; Cheng-Jian Xu; Mihai G Netea; Joppe W Hovius; Leo A B Joosten; Yang Li

doi:10.1038/s41467-024-47505-z

A comprehensive genetic map of cytokine responses in Lyme borreliosis

Nat Commun. 2024 May 7;15(1):3795. doi: 10.1038/s41467-024-47505-z.

Authors

Javier Botey-Bataller^#^{1

2

3}, Hedwig D Vrijmoeth^#^{1

4}, Jeanine Ursinus^{4

5}, Bart-Jan Kullberg¹, Cees C van den Wijngaard⁴, Hadewych Ter Hofstede¹, Ahmed Alaswad^{2

3}, Manoj K Gupta^{2

3

6}, Lennart M Roesner^{6

7}, Jochen Huehn^{6

8}, Thomas Werfel^{6

7}, Thomas F Schulz^{6

9}, Cheng-Jian Xu^{1

2

3}, Mihai G Netea^{1

10}, Joppe W Hovius⁵, Leo A B Joosten^{1

11}, Yang Li^{12

13

14

15}

Affiliations

¹ Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands.
² Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
³ TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
⁴ National Institute for Public Health and Environment (RIVM), Center for Infectious Disease Control, Bilthoven, the Netherlands.
⁵ Department of Internal Medicine, Division of Infectious Diseases & Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
⁷ Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
⁸ Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
⁹ Institute of Virology, Hannover Medical School, Hannover, Germany.
¹⁰ Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
¹¹ Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
¹² Department of Internal Medicine and Radboudumc Community for Infectious Diseases, Radboud university medical center, Nijmegen, the Netherlands. [email protected].
¹³ Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. [email protected].
¹⁴ TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. [email protected].
¹⁵ Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Anti-Bacterial Agents
Borrelia burgdorferi / genetics
Borrelia burgdorferi / immunology
Cytokines* / genetics
Cytokines* / metabolism
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Interleukin 1 Receptor Antagonist Protein / genetics
Interleukin-10 / genetics
Lyme Disease* / genetics
Lyme Disease* / immunology
Lyme Disease* / microbiology
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci*

Substances

Cytokines
Interleukin-10
Interleukin 1 Receptor Antagonist Protein
Anti-Bacterial Agents
IL10 protein, human

Grants and funding

948207/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)