Abstract
BACKGROUND: Spaceflight environments pose unique physiological challenges due to al-tered gravity and radiation exposure. METHODS: To investigate how these abiotic stressors interact with viral infections, we ana-lyzed the transcriptomic response of Caenorhabditis elegans acclimated to low-shear mod-eled microgravity (LSMMG) and radiologically shielded environments (RSE), after being infected with Orsay virus (OrV). Using RNA-sequencing, we characterized gene expres-sion profiles across both single and combined stress conditions. RESULTS: Both LSMMG and RSE elicited distinct stress responses, including the modula-tion of oxidative stress, lipid metabolism, and immune pathways. The OrV infection alone induced robust transcriptional changes, but its impact was significantly attenuated when combined with abiotic stress, suggesting an antagonistic interaction. Notably, proviral genes such as drl-1, fat-7, and hipr-1 were downregulated under RSE and LSMMG condi-tions, potentially impairing the viral replication. Gene ontology analyses revealed enrich-ment in immune effectors, RNA metabolism, and proteostasis-related pathways, particular-ly under RSE. Viral load and RNA2/RNA1 ratios were reduced in both stress conditions, indicating a shift in viral replication dynamics. Moreover, genomic diversity and defective viral genome formation were affected differentially, with stress conditions leading to in-creased genetic diversity and structural variation. DISCUSSION: These findings suggest that acclimation to simulated off-Earth conditions primes the host for a dampened response to acute viral infections, potentially through re-source reallocation and transcriptional attenuation. This study provides transcriptomic insight into viral infections under space-relevant conditions, highlighting complex interac-tions between stressors and their implications for host-pathogen dynamics in extraterres-trial environments.