People react very differently to an infection with the Borrelia bacterium that causes Lyme disease. Researchers at Radboud university medical center, the University Medical Center Groningen (UMCG) and the Broad Institute of MIT and Harvard have investigated this varying response, and their results are published in Cell Host & Microbe. Age, genetic disposition and previous Lyme infections play an important role. However, despite the large differences observed, the Borrelia bacterium has a clear effect on the immune system’s energy regulation, opening up opportunities for research into better detection of Borrelia infections.
One million people are bitten by a tick in the Netherlands each year, and about one in five of these ticks are carriers of the Borrelia bacterium. The symptoms after an infection vary widely: for example, many people have a red ring or patch around the bite, but some do not. This can make it difficult to give a correct diagnosis.
The variation in immune response can be largely explained by differences in the production of cytokines, the most important signalling molecules in our immune system. The Human Functional Genomics Project, run by professors Mihai Netea and Leo Joosten at Radboud university medical center, UMCG Professor Cisca Wijmenga and Professor Ramnik Xavier at the Broad Institute of MIT and Harvard investigated how differences in cytokine production during a Borrelia infection in 500 healthy volunteers can be explained. Leo Joosten: “Forest rangers, who may receive as many as 35 tick bites per day, also took part in an additional study. Some of them had never had Lyme disease, even though the chance of infection was high.”
Age and genes
First of all, the immune response to Lyme disease appears to be strongly age-related. Production of the cytokine IL-22 deceases with age, reducing the immune system’s defence against the Borrelia bacteria. The researchers also found a genetic variation that increases production of the HIF-1a protein during a Borrelia infection. This protein causes the amount of lactic acid in the cell to increase, which normally only happens at low oxygen levels. This results in an energy deficiency in the immune cells and therefore a reduction in the production of IL-22 and other inflammatory proteins.
Detection and treatment
This effect on the metabolism of immune cells is specific to the Borrelia bacterium, which opens up possibilities for research into the better detection and treatment of a Borrelia infection. Leo Joosten: “It is not possible to measure IL-22 in patient’s blood so we have no new test. We do however want to look at whether blocking the lactic acid route could help, but that is difficult to do at cell level. Another way is to strengthen the immune system by raising the levels of IL-22 but we would rather find ways to increase the immune system’s ability to kill the Borrelia bacteria.”
It is interesting that previous Borrelia infections do not seem to provide protection from Lyme disease. Leo Joosten: “We had expected that people with Borrelia antibodies in their blood would have a stronger immune response to the Borrelia bacteria. However, that is not the case. It seems that the Borrelia bacterium does not cause improved resistance. We hope that further research will show how previous Lyme infections specifically affect the immune system.”
Article: Functional and Genomic Architecture of Borrelia burgdorferi-Induced Cytokine Responses in Humans, 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, Cell Host & Microbe, doi: 10.1016/j.chom.2016.10.006, published 3 November 2016.