Circulating levels of a blood cytokine could help identify patients at particularly high risk of death after contracting a common yeast infection, study findings suggest.
The multifunctional cytokine Meteorin-like (METRNL)—also known as interleukin-41—could improve the precision medicine management of fungal disease, the researchers report in Science Translational Medicine.
METRNL could be used to guide risk stratification in patients and offers the potential to manage Candida yeast infection through targeted METRNL blocking.
In this way, it could be used in a personalized theranostic manner, combining diagnosis and therapy in a single approach.
“Our study suggests that blood-circulating METRNL might represent a previously unrecognized, attractive biomarker for identification of a group of patients presenting a higher risk of mortality,” reported Jiayu Liu, PhD, from the First Affiliated Hospital of Chongqing Medical University, and co-workers.
They added: “In human patients with candidemia who expressed high blood circulating METRNL concentrations, initial serum METRNL appeared to be a potential prognosis biomarker of candidemia.”
Invasive candidiasis is a serious fungal infection caused when Candida yeasts—which commonly live on the skin and the body—overgrow and entering the bloodstream or spread to internal organs.
It affects 1.5 million people annually, causing close to a million deaths. Risk is particularly high among immunocompromised patients and antifungal drug resistance to Candida species is a growing worry.
Noting that C. albicans—a pathogenic yeast common in human gut flora— is the predominant cause of candidiasis, Liu and team examined how METRNL might aid the development of biomarker-guided antifungal therapy using studies in mice and humans.
They research showed METRNL was pivotal regulator for invasive candidiasis, acting as a disease-promoting immune checkpoint to facilitate invasive yeast infection.
METRNL was expressed in mice during bloodstream infection with C. albicans, with animals lacking the cytokine protected from invasive infection.
Blocking the cytokine using a neutralizing antibody had a positive impact on invasive C. albicans infection, with METRNL aggravating invasive C. albicans pathology.
Its overexpression promoted invasive C. albicans infection, negatively regulating the antifungal activity of macrophages and aiding infection through the macrophage KIT receptor.
Further investigation revealed METRNL inhibited the antifungal activity of macrophages through the stem cell factor receptor KIT and STAT3.
Specifically, METRNL downregulated dectin-1 expression through STAT3 signaling in macrophages after fungal activation. The down-regulated dectin-1 expression in macrophages mediated by METRNL compromised the action of phagocytosis and ability to kill the yeast.
In two independent cohorts, patients with candidemia had elevated circulating METRNL concentrations compared with those with bacteremia or healthy volunteers. In both cohorts, higher circulating METRNL concentrations were associated with poor survival.
The researchers concluded: “Together, our study findings show the detrimental role of METRNL in candidiasis pathophysiology as a disease-promoting immune checkpoint that can be inhibited to protect against fatal C. albicans sepsis.”
They added: “METRNL appears as a promising biomarker that may enable personalized risk assessment and prognosis of patients with candidemia.”
