The role of fungal viruses in shaping fungal pathogenesis and mammalian host responses

Projektinformationen

MycoViralPath

ID Finanzhilfevereinbarung: 101077734

DOI

10.3030/101077734

EK-Unterschriftsdatum 11 August 2023

Startdatum 1 September 2023

Enddatum 31 August 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 673 925,00

EU-Beitrag

€ 1 673 925,00

Koordiniert durch

THE HEBREW UNIVERSITY OF JERUSALEM
Israel

Periodic Reporting for period 1 - MycoViralPath (The role of fungal viruses in shaping fungal pathogenesis and mammalian host responses)

Berichtszeitraum: 2023-09-01 bis 2026-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Fungal infections represent a growing public health challenge, contributing to over 1.6 million deaths annually and affecting more than a billion people worldwide, with mortality rates from invasive cases reaching up to 50%. This threat is amplified by the rise in immunocompromised populations, such as those with cancer or undergoing transplants, and the difficulty in developing effective treatments due to fungi’s biological similarities with human cells. Traditional antifungal therapies often fall short, necessitating innovative strategies to combat these pathogens.

The MycoViralPath project seeks to address this critical gap by exploring a previously overlooked aspect of fungal biology: the role of mycoviruses—viruses that infect fungi—in shaping fungal behavior and disease. Our hypothesis is that these viruses, ubiquitous in nature, may influence the pathogenicity of Aspergillus fumigatus, a common soil fungus that causes severe lung infections in vulnerable individuals. Unlike conventional approaches, we propose that understanding the dynamic interplay between mycoviruses, their fungal hosts, and mammalian immune responses could unlock new ways to manage fungal diseases.

The project’s objectives are to investigate how mycoviruses modulate fungal fitness and virulence, identify the antiviral mechanisms fungi employ against these viruses, and determine how mycoviral infections alter mammalian host responses. Using advanced single-cell tracking tools, including fluorescent probes, we aim to map these complex interactions in vivo for the first time. This approach promises to reveal critical insights into pathogen evolution and host adaptation, potentially paving the way for novel therapeutic strategies that target mycoviruses or fungal antiviral defenses. By tackling the rising burden of fungal infections, MycoViralPath aims to offer hope for improved treatments and better outcomes for millions at risk.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The MycoViralPath ERC project aims to elucidate the molecular mechanisms by which mycoviruses influence fungal fitness, virulence, and host adaptation; identify fungal antiviral mechanisms; and determine how mycoviral infection shapes mammalian antifungal responses, using Aspergillus fumigatus as a model.
After approximately 36 months from the start of the project, we have made significant progress toward objectives 1 and 3. We confirmed the presence of the dsRNA polymycovirus AfuPmV-1M in the Af293 strain and generated congenic virus-cured and re-infected strains using cycloheximide and ribavirin treatments, verified through RT-PCR, RT-qPCR, and whole-genome sequencing. These strains enabled detailed phenotypic analyses, revealing that AfuPmV-1M enhances fungal conidiation through upregulated expression of the central regulatory gene brlA, increases DHN-melanin production via elevated pksP and arb2 levels, and confers resistance to oxidative and heat stress. In vivo, the virus promotes fungal survival in the murine lung (immunosuppressed and immunocompetent), leading to hypervirulence in an immunosuppressed mouse model of invasive pulmonary aspergillosis. Additionally, antiviral treatment with ribavirin during infection reduced viral load, diminished fungal virulence, and improved host survival, highlighting mycoviruses as modulators of mammalian disease outcomes. These findings were published in a peer-reviewed article, demonstrating that mycoviruses act as molecular drivers of fungal pathogenicity.
In parallel, we developed fluorescent probes for single-cell tracking of mycoviral infection, fungal physiology, and host interactions, laying the foundation for in vivo mapping of the virus-fungus-host pathosystem.
Because we are midway through the project, efforts to fully address objective 2 (identification of fungal antiviral mechanisms) and the remaining aspects of objectives 1 and 3 (e.g. detailed host adaptation and comprehensive immune response modulation) are ongoing, with experiments in fungal and mammalian antiviral signaling currently in progress.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our discovery that the dsRNA mycovirus AfuPmV-1M acts as a molecular 'backseat driver' enhancing A. fumigatus fitness, stress tolerance, and virulence in mammalian hosts fundamentally shifts paradigms of fungal pathogenesis. This is the first demonstration of mycovirus-mediated hypervirulence in a human fungal pathogen, revealing upregulated conidiation via brlA, boosted DHN-melanin production, and improved survival in oxidative/heat stress and murine lungs.
Critically, antiviral ribavirin treatment reduced viral load, fungal burden, and host mortality, paving a novel pathway for therapies targeting mycoviruses to combat invasive aspergillosis and antifungal resistance.