CAndida albicans It is a common yeast found in the human microbiome. However, in people with weakened immune systems, fungi It can cause severe and sometimes fatal yeast infections.
As eukaryotes, treating fungal infections is difficult because some potential drug targets are similar to human cellular components. Additionally, many fungi also form biofilms. The thick matrix surrounding these dense fungal colonies limits access from host immune cells. Additionally, biofilms produce signaling molecules that facilitate communication across the biofilm.
One such molecule is produced. C. albicans Farnesol was developed by a team of researchers. Oliver KurzaiThe laboratory at the University of Würzburg was previously Monocyte differentiation disorder of dendritic cells (DC), which reduces inflammatory activity.1 However, it was unclear how exactly this microbial messenger achieved this attenuation. Now, in a study published in mBioThe research group showed that farnesol alters lipid metabolic pathways within DCs, which causes mitochondrial dysfunction and reduced DC activity.2
“The field has mainly focused on what’s beneath the surface. candida And what is on the surface of dendritic cells?” Jatin VyasHe was a fungal immunologist at Harvard Medical School but was not involved in the study. Vyas added that lipids are often overlooked in many answers, which makes the study novel.
Searching the literature for clues to explain farnesol’s immune-altering effects, Kurzai’s team discovered another signaling molecule, a lipid, that similarly interferes with the inflammatory activity of DCs. Sphingosine 1-phosphate (S1P).3 This endogenous sphingolipid decreased the expression of DC receptor molecules and inflammatory cytokines. The researchers were interested in whether farnesol also acts on this sphingolipid pathway.
When the researchers applied farnesol to monocytes undergoing differentiation into DCs, they found that the molecule reduced the production of ceramide, a metabolite of sphingolipids in the S1P pathway. Farnesol also inhibited the activity of dihydroceramide desaturase (Des), an enzyme that converts lipid intermediates to ceramide.
“Farnesol had a very strong effect on the sphingolipid pathway, which affected downstream or other metabolism,” he said. maria buttlinerwho was a co-author on the study and a graduate student in Kurzai’s lab.
The research team wanted to investigate the mechanism by which farnesol reduces Des activity. They knew that this molecule was also known to promote cellular reactive oxygen species (ROS) and reduce Des function, so the research team investigated whether these two were linked in the current model. I did. They found that farnesol induced mitochondrial ROS, but reducing these ROS with antioxidants restored Des activity. These findings linked impaired lipid metabolism and mitochondrial dysfunction through this fungal signaling molecule.
Kurzai and colleagues previously showed that farnesol treatment reduced inflammatory activity in DCs, which subsequently reduced interferon gamma responses from T cells. In this study, by mimicking the effects of farnesol on Des using chemical inhibitors, we demonstrated that fungal molecules achieve this immunosuppression through Des inhibition.
“For me, this is really exciting,” Vyas said. “The secretions secreted by these organisms (fungi and bacteria) affect our cells long before they actually enter our cells. [physical] contact. But as a doctor who treats fungal infections, he’s interested in seeing what effect farnesol has. C. albicans infection. Indeed, Kurzai’s team is interested in extending their observations to mouse models by introducing: C. albicans We will examine mutants that do not produce farnesol to investigate how they alter infection.
moreover, C. albicans recently thought to be associated with worse outcomes COVID-19 (new coronavirus infection) and alcohol related liver disease.4,5 “because [C. albicans] “It appears to have systemic effects, and it will be very interesting to know which of the molecules it produces mediate these effects.” Natalie Nieuwenhuizenan immunologist at the University of Würzburg and co-author of the study. “It will be interesting to see how this affects other diseases, both positively and negatively.”
