aspirateAndida albicans It is a common yeast found in the human microbiome. However, in people with weakened immunity, mold It can cause serious and sometimes fatal yeast infections.
Fungal infections are difficult to treat because, as eukaryotes, many potential drug targets resemble human cellular components. Many fungi also form biofilms. The thick matrix surrounding these dense fungal colonies limits access from the host’s immune cells. Moreover, biofilms produce signaling molecules that facilitate communication throughout the biofilm and beyond.
One such molecule produced by C. albicans This is Farnesol developed by researchers. Oliver KurzaiThe laboratory at the University of Würzburg previously Impaired monocyte differentiation of dendritic cells (DC), reduces inflammatory activity.1 However, it is unclear how exactly these microbial messengers perform this buffering function. now, MbioThe group showed that farnesol alters lipid metabolism pathways inside DCs, resulting in mitochondrial dysfunction and impaired DC activity.2
“Much of the focus in the field was primarily on the surface. candida And what’s on the surface of dendritic cells,” he said. Jatin ByasThe fungal immunologist at Harvard Medical School was not involved in the study. Vyas added that geology was often overlooked in many responses, adding to the novelty of the work.
While searching for clues in the literature to explain farnesol’s immune-altering effects, Kurzai’s team discovered another signaling molecule that similarly interferes with DC inflammatory activity: lipids. Sphingosine 1-phosphate (S1P).3 These endogenous sphingolipids reduced the expression of DC receptor molecules and inflammatory cytokines. The researchers wondered whether farnesol also acted on this sphingolipid pathway.
When the research team applied farnesol to monocytes differentiating into DCs, they found that this molecule reduced the production of ceramide, a sphingolipid metabolite in the S1P pathway. Farnesol also inhibited the activity of dihydroceramide desaturase (Des), an enzyme that converts lipid intermediates to ceramides.
“Farnesol had a very strong effect on the sphingolipid pathway, which then affected downstream or other metabolism,” he said. Maria BatlinerA co-author who was a graduate student in Kurzai’s lab.
The team wanted to explore the mechanism by which farnesol reduces Des activity. Since they knew that the molecule promotes cellular reactive oxygen species (ROS), which have been shown to reduce Des function, the team investigated whether these two were relevant in the current model. They found that farnesol induced mitochondrial ROS, but reducing these species with antioxidants rescued Des activity. These findings linked lipid metabolism disorders and mitochondrial dysfunction through fungal signaling molecules.
Kurzai and his team have previously shown that farnesol treatment reduces DC inflammatory activity and thereby the interferon gamma response of T cells. In this study, by mimicking the effect of farnesol on Des using a chemical inhibitor, we demonstrated that fungal molecules achieve this immunoattenuation through Des inhibition.
“For me, this is really exciting,” said Vyas. “Secretions from these organisms (fungi, bacteria) act on our cells long before they actually enter the cells. [physical] Contact.” But as a doctor who treats fungal infections, he’s interested in finding out what effect farnesol has. C. albicans infection. In fact, Kurzai’s team is interested in extending their observations to mouse models. C. albicans We use mutants that do not produce farnesol to investigate how infection changes.
Also, overgrowth C. albicans More recently, it has been associated with worse outcomes. covid-19 and alcohol-related liver disease.4,5 “because [C. albicans] “It appears to have systemic effects, but it would be really interesting to know which of the molecules it makes might mediate these effects.” Natalie Neuenhuizenis an immunologist at the University of Würzburg and co-author of the study. “It would be interesting to know how this affects other diseases, in good or bad ways.”
