Genome-wide screen uncovers novel host factors for L-A virus maintenance and a mutualistic-symbiosis relationship in yeast

Viruses are often regarded as obligate intracellular parasites that exploit host resources for their own propagation. However, emerging evidence suggests that virus–host interactions can be more complex than simple antagonism. Here, we performed a genome-wide screen in Saccharomyces cerevisiae to identify host factors required for the maintenance of the L-A double-stranded RNA virus, a persistent and non-lytic resident of most laboratory yeast strains. Using two complementary mutant collections encompassing ∼6,000 yeast genes (∼93% genome coverage), we identified 96 host genes essential for L-A maintenance, spanning diverse biological functions. Transcriptome profiling revealed that the presence of L-A virus alters the host stress-response gene expression program. Strikingly, competitive fitness assays under environmental stress conditions showed that L-A enhances host stress tolerance, revealing a previously unrecognized mutualistic relationship. Together, our findings redefine the L-A–yeast interaction as a form of stable mutualism and highlight the utility of functional genomics and systems-level approaches in uncovering hidden dimensions of virus–host coevolution.