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How do we combat fungal infections?

Since fungi are eukaryotic and evolved in close association with their mammalian hosts, most essential fungal molecular targets for drug development bear a considerable risk of cross-target host toxicity. The current arsenal of antifungal drugs and therapies are limited in number and diversity, and their efficacy is severely hampered by host toxicity, fungistatic rather than fungicidal activity and drug resistance. our overarching goal is to identify novel fungal-specific targets for the development of fungal-selective, pan-antifungal drugs. To reduce our reliance on pathogen-targeted agents, we propose an integrated approach that will combine therapeutic interventions to boost hosts’ anti-fungal immune response and selective targeting of fungal essential pathways.

Visualizing infection outcome at single-cell resolution
The interaction of microbes with the immune system is multifactorial and depends not only on microbial features but also on the immune state of the host and on environmental factors. The outcome of each individual encounter is context-dependent.   Additionally, the microbial and host cell populations are incredibly heterogeneous, which may have significant phenotypic consequences leading to diverse outcomes upon encounter of fungal conidia with immune cells. 
We are trying to define how all these components work together to determine the outcome of the interaction, or in other words,  what makes a microbe a pathogen?
We have developed a suite of fluorescent probes that enable tracking of these intricate interactions at single-cell resolution, and assessment of the physiological state of the fungus and immune cells in the host tissue.

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Microbial population heterogeneity (transcriptional, protein, phosphorylation, metabolic)

Host population 
heterogeneity

Regulated cell death pathways and fungal  pathogenesis
We discovered that the mammalian immune surveillance against inhaled fungal conidia triggers regulated cell death (RCD
) pathway in fungal cells. In response, the fungal anti-RCD machinery counteracts host defenses and protects the fungus from host-induced RCD by facilitating phagosomal escape and invasive aspergillosis (IA).   Therefore, targeting fungal RCD pathways and the corresponding host defenses may provide novel therapeutic strategies to treat fungal infections.   
Related projects are aimed at  (1) Elucidating the fungal RCD pathways  to identify fungal-specific key players vital for fungal survival within the lung. (2)  Identify host effectors and compounds necessary for induction of fungal RCD. 

Figure S10. A model showing the role of PCD in early events of A. fumigatus infection new

Fungal viruses (mycoviruses) and fungal virulence
Mycoviruses can transform fungal virulence, yet very little is known of the intricate interplay between the mycovirus, the fungus, and the mammalian immune system, and how it affects fungal pathogenesis and host adaptation. We are using a powerful combination of cutting-edge methodologies for the detection and visualization of mycoviral infection and of fungal physiology at single-cell resolution, to tackle fundamental questions in host-mycovirus biology:
*How does mycoviral infection affect fungal fitness and virulence? How does it inform host preference?
*Do fungal pathogens have a designated anti-mycoviral mechanism? Do they have a common ancient ancestry of innate immunity?
*How is mycoviral infection sensed by the immune system?
*How does it affect the infection outcome? Can antiviral therapy mitigate detrimental immune responses? 

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