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

Publication date: Available online 3 November 2016
Source:Cell Host & Microbe
Author(s): Marije Oosting, Mariska Kerstholt, Rob ter Horst, Yang Li, Patrick Deelen, Sanne Smeekens, Martin Jaeger, Ekta Lachmandas, Hedwig Vrijmoeth, Mihaela Lupse, Mirela Flonta, Robert A. Cramer, Bart Jan Kullberg, Vinod Kumar, Ramnik Xavier, Cisca Wijmenga, Mihai G. Netea, Leo A.B. Joosten
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.

Graphical abstract

Teaser

Cytokine-mediated processes regulate both host defense and long-term inflammatory complications in Lyme disease caused by Borrelia burgdorferi. Oosting et al. use functional genomics to reveal the architecture of cytokine production during Borrelia infection of human primary leukocytes. Their data suggest a connection between cellular glucose metabolism and Borrelia-induced cytokine production.


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