Cosmic silence and viral noise: transcriptomic crosstalk in Caenorhabditis elegans under simulated space conditions

Spaceflight environments pose unique physiological challenges due to altered gravity and radia-tion exposure. To investigate how these abiotic stressors interact with viral infection, we analyzed the transcriptomic response of Caenorhabditis elegans acclimated to simulated microgravity ({micro}G) and below-background muon radiation flux (BBR), upon infection with Orsay virus (OrV). Using RNA-seq, we characterized gene expression profiles across single and combined stress condi-tions. Both {micro}G and BBR elicited distinct stress responses, including modulation of oxidative stress, lipid metabolism, and immune pathways. OrV infection alone induced robust transcrip-tional changes, but its impact was significantly attenuated when combined with either abiotic stress, suggesting antagonistic interactions. Notably, proviral genes such as drl-1, fat-7 and hipr-1 were downregulated under BBR and {micro}G, potentially impairing viral replication. Gene ontology analyses revealed enrichment in immune effectors, RNA metabolism, and proteostasis-related pathways, particularly under BBR. Viral load and RNA2/RNA1 ratios were reduced in both stress conditions, indicating a shift in viral replication dynamics. Moreover, genomic diversity and de-fective viral genome formation were differentially affected, with increased genetic diversity and structural variation under stress. These findings suggest that acclimation to off-Earth conditions primes the host for a dampened response to an acute viral infection, potentially through resource reallocation and transcriptional attenuation. This study provides transcriptomic insight into viral infection under space-relevant conditions, highlighting complex stress interactions and their im-plications for host-pathogen dynamics in extraterrestrial environments.