Project description:Mucormycosis is an increasingly common, life-threatening fungal infection caused by fungi belonging to the subphylum Mucormycotina, order Mucorales. The major risk factors for mucormycosis include uncontrolled diabetes mellitus, treatment with corticosteroids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematological disorders, and deferoxamine-therapy in patients receiving hemodialysis. Amphotericin B (AmB) remains the only antifungal agent approved for the treatment of invasive mucormycosis. Because fungi belonging to the mucorales order are relatively resistant to AmB, high doses are required, which frequently causes nephrotoxicity and other adverse effects. In the absence of surgical removal of the infected focus (such as excision of the eye in patients with rhinocerebral mucormycosis), antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose AmB, the mortality associated with mucor¬mycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Rhizopus oryzae is by far the most common organism isolated from patients with mucormycosis, and is responsible for approximately 70% of all cases of mucormycosis. Recent epidemiological data collected from transplant centers have demonstrated a striking increase in the number of reported cases of mucormycosis. Furthermore, mucormycosis outbreaks are also known to follow natural disasters as was the case following the tsunami that devastated Indonesia in 2004 and the tornadoes that destroyed Joplin, Missouri in June 2011. Hence, there exists a large impetus to identify particular virulence factors and biomarkers associated with mucormycosis, which would lead to a rational approach to develop new antifungals and vaccines to prevent deaths specifically due to mucormycosis. In order to better understand the complex nature of the host pathogen interaction during mucormycosis, we performed dual species RNA-seq on 5 different Mucorales strains during in vitro infection of endothelial or epithelial cells.

Project description:Objective:Metabolic associated fatty liver disease (MAFLD) affects approximately 25% of the global population, posing a serious threat to public health, and its pathogenesis remains largely unknown. Gut fungi play a significant role in the development of liver diseases, but the gut microbial community and its functions in MAFLD patients are not yet clear.Methods:We performed fungal ITS sequencing on fecal samples from 107 MAFLD patients and 120 healthy control (HC), matched for region, ethnicity, age, and sex. A high-fat diet-induced MAFLD mouse model was established and multi-omics techniques such as Liver transcriptome sequencing, qPCR, Western blot, and immunofluorescence were employed to validate the molecular mechanisms of key gut fungi involved in MAFLD. Results:MAFLD patients exhibited reduced species richness and diversity compared to HC. The gut microbiome of MAFLD patients was characterized by an increase in the harmful fungal genus Rhizopus, specifically the harmful fungi Rhizopus microsporus var. rhizopodiformis and Rhizopus microsporus var. chinensis, which positively correlated with the degree of steatosis and BMI. Transplantation of fecal microbiota from MAFLD subjects into ABX mice led to the onset of MAFLD-like symptoms, whereas B amphotericin (AMP) administration alleviated disease progression. Gavage with Rhizopus microsporus var. rhizopodiformis significantly exacerbates gut microbiota dysbiosis and metabolic disorders, disrupted the intestinal barrier and activated liver SREBP-1c, thereby upregulating key lipid synthesis enzymes ACC1 and FASN. This activation occurred through a pro-inflammatory cascade involving the liver macrophage LPS-TLR4-NF-κB axis, amplification of inflammatory signals, and neutrophil degranulation.Conclusion:Rhizopus microsporus var. rhizopodiformis promotes hepatic lipid synthesis by upregulating hepatic neutrophil degranulation and facilitating SREBP-1c activation pathway.

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Genome-wide Discovery of lncRNAs in Mucorales Reveals Essential Roles in EDF Biology

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