Functional and Genomic Architecture of Borrelia burgdorferi-Induced Cytokine Responses in Humans

Cell Host Microbe. 2016 Dec 14;20(6):822-833. doi: 10.1016/j.chom.2016.10.006. Epub 2016 Nov 3.

Abstract

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.

Keywords: Borrelia burgdorferi; HIF-1α; Lyme disease; cytokines; glucose metabolism; host defense.

MeSH terms

  • Age Factors
  • Animals
  • Blood
  • Borrelia burgdorferi / genetics*
  • Borrelia burgdorferi / immunology*
  • Borrelia burgdorferi / pathogenicity
  • Borrelia burgdorferi Group / genetics
  • Borrelia burgdorferi Group / pathogenicity
  • Cell Line
  • Cell Survival
  • Chromosome Mapping
  • Cytokines / analysis
  • Cytokines / biosynthesis*
  • Cytokines / blood
  • DNA, Bacterial
  • Genome, Bacterial
  • Genomics*
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interferon-gamma
  • Interleukin-17 / metabolism
  • Interleukin-6 / metabolism
  • Interleukins / metabolism
  • Lactic Acid / metabolism
  • Leukocytes
  • Lyme Disease / immunology*
  • Lyme Disease / microbiology
  • Mice
  • Monocytes / immunology
  • T-Lymphocytes / immunology
  • Transcriptome

Substances

  • Cytokines
  • DNA, Bacterial
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-17
  • Interleukin-6
  • Interleukins
  • Lactic Acid
  • Interferon-gamma
  • Glucose
  • interleukin-22