The Therapeutic Administration of Lactobacillus brevis ZG2488 Suppresses Influenza A Virus Replication Through a Viability-Dependent Host Transcriptional Modulation Mechanism

Influenza A virus (IAV) remains a major global threat, highlighting the need for host-targeted antiviral strategies. While some probiotics offer prophylactic protection, their therapeutic potential post-infection is poorly understood. Here, we investigated human-derived <i>Lactobacillus brevis</i> ZG2488 for its antiviral potential against IAV. Strikingly, a more pronounced reduction in viral titer was observed when live bacteria were administered therapeutically post-infection, compared to preventive pretreatment. Transcriptomic analysis suggested that the therapeutic effect of viable bacteria was associated with a modulated host response, including the downregulation of specific host factors implicated in viral replication (e.g., <i>KPNA2</i>, <i>NUP98</i>, <i>EIF2S1</i>) and a delayed interferon-beta (IFNB1) induction. In contrast, preventive effects appeared to be mediated by heat-stable components. These findings highlight a viability-dependent mode of action for <i>L. brevis</i> ZG2488 and contribute to the growing evidence that certain probiotics may exert antiviral effects through targeted host modulation rather than solely through broad immune activation.