Immune system can be modulated by manipulating metabolism

In an attempt to fight a serious bacterial infection, the immune system can become so overactivated that the resulting inflammatory response can quickly lead to death.

Now, Austrian researchers have revealed that such an excessive response can be modulated by targeted manipulation of sugar metabolism to produce an immune response that efficiently eliminates the pathogens without causing any harmful secondary reactions. Their results have been published in the journal PLOS ONE.

Scientists from the Medical University of Vienna (MedUni Vienna), supervised by Gerhard Zlabinger, achieved their goal by administering a specific sugar compound, called 2-Deoxy-D-glucose (2-DG), during a Listeria infection in mice. This sugar molecule differs from glucose in that it lacks a hydroxyl group, consisting of one hydrogen atom and one oxygen atom.

Administering 2-DG, which serves to inhibit glycolysis, causes increased production of interleukin-12 (IL-12), a pro-inflammatory cytokine, while suppressing the production of interleukin-10, an anti-inflammatory cytokine. One of the main functions of IL-12 is to trigger a specific T-cell immune response, which is part of the cellular immune response, to specifically boost the defence mechanisms that serve to eliminate intracellular pathogens (such as Listeria).

“The administration of 2-DG apparently changes the nature of the immune response and hence also the intensity of the inflammatory process,” explained Zlabinger. “Inflammation is modulated so that the immune system is once again able to manage the situation itself, without allowing the infection to have a lethal outcome. It is as if we are pressing the reset button, thereby preventing excessive inflammatory responses.”

The underlying mechanism behind this is not yet known, although lead author Johannes Kovarik hypothesises that the expression of IL-12, which can be formed by two separate chains (p35 and/or p40), probably plays a role. Following administration of 2-DG, only p40 is upregulated, while no p35 is produced. This modified cytokine profile (there is also a simultaneous increase in IL-23 expression) could subsequently bring about modified recruitment of immune cells and hence have a decisive influence on the intensity of the immune response.

“Our study is an excellent example of the importance of the immune metabolism, that is to say the modified metabolism of essential nutrients by activated immune system cells,” said Thomas Decker, a co-author on the study from the University of Vienna. “We were amazed by the extent to which mice became resistant to bacterial infections due to inhibition of the glucose metabolism. This metabolic reversal creates a push-pull effect: increased production of activating mediators with simultaneous inhibition of immunosuppressive mediators.”

Manipulation of the sugar metabolism and associated modulation of the immune system could open up new options for treating specific infectious as well as autoimmune diseases in the future, according to the researchers. Further work will be required for this, with some projects already underway at MedUni Vienna’s Institute of Immunology.