Abstract
The filamentous fungal pathogen Aspergillus fumigatus is one of the most common causal agents of invasive fungal infection in humans; the infection is associated with an alarmingly high mortality rate. In this study, we investigated whether a mycovirus, named AfuPmV-1M, can reduce the virulence of A. fumigatus in a mouse infection model. AfuPmV-1M has high sequence similarity to AfuPmV-1, one of the polymycovirus that is a capsidless four-segment double-stranded RNA (dsRNA) virus, previously isolated from the genome reference strain of A. fumigatus, Af293. However, we found the isolate had an additional fifth dsRNA segment, referred to as open reading frame 5 (ORF5), which has not been reported in AfuPmV-1. We then established isogenic lines of virus-infected and virus-free A. fumigatus strains. Mycovirus infection had apparent influences on fungal phenotypes, with the virus-infected strain producing a reduced mycelial mass and reduced conidial number in comparison with these features of the virus-free strain. Also, resting conidia of the infected strain showed reduced adherence to pulmonary epithelial cells and reduced tolerance to macrophage phagocytosis. In an immunosuppressed mouse infection model, the virus-infected strain showed reduced mortality in comparison with mortality due to the virus-free strain. RNA sequencing and high-performance liquid chromatography (HPLC) analysis showed that the virus suppressed the expression of genes for gliotoxin synthesis and its production at the mycelial stage. Conversely, the virus enhanced gene expression and biosynthesis of fumagillin. Viral RNA expression was enhanced during conidial maturation, conidial germination, and the mycelial stage. We presume that the RNA or translation products of the virus affected fungal phenotypes, including spore formation and toxin synthesis. To identify the mycovirus genes responsible for attenuation of fungal virulence, each viral ORF was ectopically expressed in the virus-free KU strain. We found that the expression of ORF2 and ORF5 reduced fungal virulence in the mouse model. In addition, ORF3 affected the stress tolerance of host A. fumigatus in culture. We hypothesize that the respective viral genes work cooperatively to suppress the pathogenicity of the fungal host.
Highlights
Aspergillus fumigatus is a ubiquitous environmental fungus that is currently the most commonly encountered mold pathogen in severely immunocompromised patients
A. fumigatus strain Af293 was obtained from the American Type Culture Collection (ATCC), strain KU was obtained from the Fungal Genetics Stock Center (FGSC), and they were stored at Medical Mycology Research Center (MMRC), Chiba University
It is possible that the study of mycoviruses could provide clinically useful information because the virus might cause hypovirulence in its fungal hosts
Summary
Aspergillus fumigatus is a ubiquitous environmental fungus that is currently the most commonly encountered mold pathogen in severely immunocompromised patients. The emergence of drug-resistant fungi and the toxic side effects of antifungal drugs are two major problems associated with the treatment of fungal infections. The development of new therapeutic strategies is urgently required. This may include the discovery of new chemotherapeutic drugs based on the identification of novel fungal targets and finding novel therapeutic methods for alleviating the pathogenic effects of fungi. One such hypothetical therapeutic strategy may include the use of mycoviruses, which can selectively infect pathogenic fungi. The majority of characterized mycoviruses of plant-pathogenic fungi have double-stranded RNA (dsRNA) genomes. Our knowledge of mycoviruses in fungal pathogens infecting animals and humans remains limited (van de Sande et al, 2010; van de Sande and Vonk, 2019)
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