How fungal infections trigger blood poisoning

Blood poisoning caused by a fungal infection is a life-threatening danger. Researchers at the University of Bern have now discovered a mechanism that helps a yeast fungus spread more easily within the body. Of all things, the immune system plays a leading role in this. These findings could open up new therapeutic avenues for blood poisoning caused by yeasts, but also for other internal fungal infections.

Read the original media release here. (in German)

Normally, the yeast Candida albicans is a harmless inhabitant of our mucous membranes. Around half of the population is colonised by it without noticing. As long as the body’s own defence system is intact, it keeps the fungus in check with ease. It becomes dangerous when the immune system is weakened. This can be the case, for example, with diseases such as AIDS or when taking medication that suppresses the immune defences.

In people with a healthy immune system, surgical procedures that damage the mucosal barrier, among other things, can favour the spread of Candida albicans . Once the yeast is in the bloodstream, it can cause blood poisoning (sepsis) and thus lead to permanent damage to the internal organs: between a third and a half of patients do not survive such fungal sepsis.

The immune system’s natural response to the invasion of pathogens is an inflammatory reaction. A sophisticated control system ensures that only invaders are fought without attacking healthy tissue at the same time. A certain protein plays a key role here, the so-called interleukin 1 receptor antagonist. This protein is the natural counterpart of the pro-inflammatory messenger substance interleukin 1. It prevents the latter from overshooting and setting off uncontrolled inflammatory reactions.

Anti-inflammatory protein weakens immune defences #

A new study led by PD Dr med. Stefan Freigang from the Institute of Tissue Medicine and Pathology (IGMP) at the University of Bern now suggests that, despite its anti-inflammatory function, the interleukin 1 receptor antagonist (IL-1Ra) helps to promote the spread of Candida albicans . IL-1Ra produced by the so-called scavenger cells (macrophages) appears to be particularly important. In mice, the researchers were able to show that the amount of these anti-inflammatory proteins in the scavenger cells increased when Candida albicans entered the bloodstream, but that they subsequently disrupted the immune defences. Specifically, they inhibited the production and swarming out of neutrophils, a subgroup of white blood cells. The neutrophils  form an important early barrier against infections by regularly patrolling the blood vessels to eliminate invading pathogens.

Mice that were genetically bred so that their scavenger cells no longer produced any of the anti-inflammatory proteins had an intact arsenal of neutrophils. Accordingly, they were able to successfully fight off an infection with Candida albicans within a short time. In the control group of normal mice that produced the anti-inflammatory protein, on the other hand, the fungi were able to spread because the neutrophils were inhibited.

Interestingly, the loss of the anti-inflammatory proteins did not lead to an overshooting inflammatory response, as would have been expected, but to a reduced one. “We explain this by the fact that there were enough neutrophils to eliminate the yeast before it could trigger a pathogenic inflammatory reaction,” says Stefan Freigang.

So when fewer anti-inflammatory proteins are produced, the neutrophils can do their work undisturbed as the “first line of defence”. However, if the proteins are produced by the scavenger cells, this weakens the immune defences. Such complex and dynamic interactions of the immune system can only be mapped in a living organism, which in this case requires animal experiments with genetically modified mice and normal mice as a control group.

A possible therapeutic approach #

The findings of the Bern researchers could enable new therapeutic approaches in the future. “Fungal sepsis is still difficult to treat and is associated with a high mortality rate. In order to develop more effective treatment strategies, we need a better understanding of the underlying disease mechanisms,” explains Stefan Freigang. In a next step, the researchers want to use samples from patients to confirm the observations from the mouse model and to investigate whether the specific protein also favours infections with Candida albicans in humans. “If this is confirmed, active substances directed against the protein could be used as a new strategy to combat the yeast and possibly other fungal infections as well,” says Freigang.

The research results were published in the journal Immunity.