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Radosa, L.

Publications and source records attributed to Radosa, L..

3 recordsLinked to original sources

The murine lung microbiome is dysbalanced by the human pathogenic fungus Aspergillus fumigatus resulting in enrichment of anaerobic bacteria

Here, we report significant changes in the composition of the lung microbiome and metabolome of mice under immune suppression, infection of immunosuppressed mice with virulent and avirulent strains of the clinically important human-pathogenic fungus Aspergillus fumigatus, and treatment with the clinically used antifungal drug voriconazole. Our data also indicate the important role of the gut microbiome for the lung homeostasis mediated by the plasma metabolome. In the lung microbiome, infection by A. fumigatus led to a significant increase of anaerobic bacteria, most prominently of Ligilactobacillus murinus, which was confirmed by the isolation of live bacteria from the murine lower respiratory tract. In vitro, L. murinus is tolerated and even internalized by alveolar epithelial cells. Co-cultivation of L. murinus and A. fumigatus led to a reduction in oxygen concentration accompanied by an increase of L. murinus cells suggesting that A. fumigatus establishes a microaerophilic niche, thereby promoting growth of anaerobic bacteria.

microbiology↗

Re-direction of phagosomes to the recycling expulsion pathway by a fungal pathogen

The analysis of host-pathogen interactions bears the potential to discover novel pathogenicity mechanisms and to obtain novel insights into basic mechanisms of cell biology. Here, we obtained unprecedented insight into both. We discovered that the HscA protein on the conidial surface of the clinically important human-pathogenic fungus Aspergillus fumigatus acts as an effector protein. It inhibits phagosome maturation and reprograms phagosomes for expulsion of conidia. HscA anchors the human p11 protein to phagosomes. p11 is a decisive factor for targeting phagosomes either to the degradative or secretory pathway. The relevance of our findings is indicated by the identification of an SNP in the non-coding region of the human p11 gene that affects its translation and is associated with heightened susceptibility to invasive pulmonary aspergillosis.

cell biology↗

Dynamic optimization reveals alveolar epithelial cells as key mediators of host defense in invasive aspergillosis

Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is a key virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we find that epithelial cells play a so far underappreciated role in fungal clearance and are potent mediators of cytokine release which we confirm ex vivo. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence.

systems biology↗