ABSTRACT: Diagnosis by metagenomic next-generation sequencing of invasive pulmonary aspergillosis in an infant with Chronic Granulomatous Disease: A case report
Project description:Diagnosis by metagenomic next-generation sequencing of invasive pulmonary aspergillosis in an infant with Chronic Granulomatous Disease: A case report
Project description:Diagnosis by metagenomic next-generation sequencing of invasive pulmonary aspergillosis in an infant with Chronic Granulomatous Disease: A case report
Project description:Diagnosis by metagenomic next-generation sequencing of invasive pulmonary aspergillosis in an infant with Chronic Granulomatous Disease: A case report Metagenome
Project description:Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. By undertaking a longitudinal case-control study, we explored the possibility to identify novel non-invasive human biomarkers candidates for IPA in patients post allogeneic stem cell transplantation (alloSCT). Using both RNA-sequencing and immunoassays, we investigated 66 blood samples of 3 probable IPA cases and 3 matched controls without Aspergillus infection. Selected potential biomarker candidates were evaluated further in additional alloSCT (n=23) and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and their appropriate control patients (n=65). Profiling analysis suggested LGALS2, MMP1 and caspase-3 as potential biomarker candidates indicating IPA in investigated alloSCT patients. Significant differences in IL-8 and caspase-3 levels were observed among CAPA patients compared to control patients. Given our conceptual work we demonstrate the value of seeking human IPA indicating biomarkers, which together with already established fungal biomarkers potentially improve the accuracy of IPA diagnostic.
Project description:In lung diseases caused by the major mould pathogen Aspergillus fumigatus the pulmonary epithelium is destroyed by invasive growth of fungal hyphae, a process thought to require fungal proteases. Here we show that the A. fumigatus pH-responsive transcription factor PacC governs expression of secreted proteases during invasive lung infections and is required for epithelial invasion and pathogenicity. In addition, A. fumigatus ΔpacC mutants aberrantly remodel the fungal cell wall during infection. This study defines distinct PacC-mediated mechanisms of host damage during pulmonary aspergillosis. ch1: treatment protocol
Project description:In lung diseases caused by the major mould pathogen Aspergillus fumigatus the pulmonary epithelium is destroyed by invasive growth of fungal hyphae, a process thought to require fungal proteases. Here we show that the A. fumigatus pH-responsive transcription factor PacC governs expression of secreted proteases during invasive lung infections and is required for epithelial invasion and pathogenicity. In addition, A. fumigatus M-NM-^TpacC mutants aberrantly remodel the fungal cell wall during infection. This study defines distinct PacC-mediated mechanisms of host damage during pulmonary aspergillosis. ch1: treatment protocol Temporal transcriptional profiling of ATCC46645 strain and isogenic M-NM-^TpacC Aspergillus fumigatus mutant during murine infection
Project description:Eosinophilia is associated with various persisting inflammatory diseases and often coincides with chronic fungal infections or fungal allergy as in case of allergic bronchopulmonary aspergillosis (ABPA). However, the interactions between eosinophils and fungal pathogen leading to release of inflammatory mediators from eosinophils are poorly understood. Therefore, we established a co-culture system of mouse bone marrow derived eosinophils (BMDE) with Aspergillus fumigatus (Af) that we used in part to analyse transcriptional regulation induced by Af.
Project description:Aspergillosis covers a range of infections cause by Aspergillus species, and in many cases can be life threatening. Individuals with weakened immune systems are particularly at risk. Dendritic cells were derived from patients with allergic brochopulmonary aspergillosis (ABPA), chronic cavitary pulmonary aspergillosis (CCPA), and asthma, as well as from healthy donors. Each sample was split in two, and one sample from each pair was cultured with Aspergillus fumigatus. RNA-sequencing was used to assess transcriptional changes in the human cells in response to pathogen challenge. Many genes known to be important in immunity were found to exhibit differential expression after fungal challenge between healthy and diseased individuals, including chemokines and C-type lectins.
Project description:The filamentous fungus Aspergillus fumigatus is the cause of a variety of pulmonary infections (chronic pulmonary aspergillosis) and life-threatening systemic infection that can infect a variety of different organs (invasive aspergillosis). A. fumigatus is widely distributed in the environment and produces large numbers of small conidia that are inhaled daily. A rapid immune response eliminates these in the immunocompetent host but in cases of pulmonary disease or immunosuppression conidia can quickly germinate and grow in the body. Statins interfere with biosynthesis of cholesterol and are therefore used in treatment of hypercholesterolemia. There is increasing evidence for the potential use of statins in preventing and treating fungal infections. The aim of this study was to assess the effect of statins on A fumigatus and to characterize the proteomic alterations occurring in A. fumigatus in response to statin. Pre-growth of A fumigatus in the presence of statin resulted in lower levels of ergosterol. Cells also showed increased permeability as measured by elevated amino acid and protein leakage. Gliotoxin release increased about nine fold in atorvastatin treated cells. Proteomic analysis revealed differential abundance of proteins involved in oxidative stress response such as glutathione S-transferase family protein (8.43 fold increase) and heat shock protein Hsp30/Hsp42 (2.02 fold increase). Protein related to secondary metabolite biosynthesis like nonribosomal peptide synthetase fmpE (3.06 increase) and 3- Aflatoxin B1-aldehyde reductase GliO-like (-2.86 fold decrease) These results indicate that statins have the ability to reduce the growth of A. fumigatus.