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 to spread more easily within the body. The immune system, of all things, plays a key role in this process. These findings could open up new therapeutic avenues for blood poisoning caused by yeasts, but also for other internal fungal infections.
Normally the yeast fungus is Candida albicans a harmless co-inhabitant of our mucous membranes. Around half of the population is colonised by it without realising it. As long as the body's own defence system is intact, it easily keeps the fungus in check. 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 defence.
In people with a healthy immune system, surgical procedures that injure the mucosal barrier can, among other things, prevent the spread of Candida albicans favour the infection. Once the yeast is in the bloodstream, it can cause blood poisoning (septicaemia) and thus lead to permanent damage to the internal organs: One third to one 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 combated without attacking healthy tissue at the same time. A key role is played by a specific protein, the so-called interleukin 1 receptor antagonist. This protein is the natural antagonist of the pro-inflammatory signalling substance interleukin 1, preventing it from overshooting the mark and triggering uncontrolled inflammatory reactions.
A new study led by PD Dr Stefan Freigang from the Institute of Tissue Medicine and Pathology (IGMP) at the University of Bern now indicates that the interleukin 1 receptor antagonist (IL-1Ra), despite its anti-inflammatory function, contributes to the spread of Candida albicans to promote the immune response. IL-1Ra, which is produced by macrophages, appears to be particularly important in this context. In mice, the researchers were able to show that the amount of these anti-inflammatory proteins in the macrophages increased when Candida albicans into the bloodstream, and that they subsequently interfered with the immune defence. They inhibited the production and swarming of neutrophils, a subgroup of white blood cells. 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 phagocytes no longer produced the anti-inflammatory proteins had an intact arsenal of neutrophils. Accordingly, they were able to prevent infection with Candida albicans successfully fight the fungi within a short period of time. In the control group with normal mice, on the other hand, which produced the anti-inflammatory protein, the fungi were able to spread due to the inhibited neutrophils.
Interestingly, the loss of the anti-inflammatory proteins did not lead to an overshooting of the inflammatory response, as would have been expected, but to a reduction. "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.
If fewer anti-inflammatory proteins are produced, the neutrophils as the "first line of defence" can do their work undisturbed. However, if the proteins are produced by the phagocytes, this weakens the immune defence. Such complex and dynamic interactions of the immune system can only be modelled in a living organism, which in this case requires animal experiments with genetically modified and normal mice as a control group.
The research findings of the Bernese researchers could enable new therapeutic approaches in the future. "Fungal septicaemia 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 investigate whether the specific protein can also cause infections in humans. Candida albicans is favoured. "If this is confirmed, active substances that target the protein could be used as a new strategy to combat the yeast fungus and possibly also other fungal infections," says Freigang.
The research results were published in the journal Immunity published.
INSTITUTE FOR TISSUE MEDICINE AND PATHOLOGY
The Institute of Tissue Medicine and Pathology (IGMP) at the University of Bern covers the entire spectrum of morphological and molecular diagnostics on tissue samples. The combination of service, teaching and research under one roof allows for close interaction and mutual inspiration. Research is concerned with the development, diagnosis and therapy of diseases. Immunopathologies, inflammatory diseases and aspects of tumour biology are the current focal points. Ex-vivo investigations are carried out on human tissue samples and experimental in-vitro and in-vivo model systems are also used. As a university centre for tissue medicine and pathology, the IGMP offers the entire spectrum of tissue examinations. Contact persons are defined for each medical speciality, who are well networked in the corresponding interdisciplinary environment.