Systemic BCG administration induces transcription factor signature in CD4T cells that cooperates with IL-12 signaling to drive antiviral Th1 differentiation.

Mycobacterium bovis bacillus Calmette-Guerin (BCG) is a form of live attenuated M. bovis-based vaccine used to prevent tuberculosis and other mycobacterial infections. BCG immunization also provides cross-protection against a broad range of viral pathogens. Recent studies show that a coordinated induction of innate and adaptive immune responses is involved, though the mechanisms are less defined. To investigate the cross-protection of BCG against virus infection, we used a mouse model of respiratory syncytial virus (RSV) infection and demonstrated that systemic administration of live BCG altered chromatin accessibility for transcriptional factor expression favoring Th1 response. Specifically, BCG-IV immunization protected mice against RSV infection. BCG immunization caused metabolic reprogramming in monocytes and neutrophils and innate immune response, leading to IL12/IL12R-mediated naïve CD4T cell differentiation to the Th1 cell population. Integrated analysis of chromatin openness and transcriptomic data revealed that BCG administration upregulated transcription factors including interferon regulatory factors (IRF1) and signal transducer and activator of transcription (STAT1 and STAT2), a signature for interferon signaling and antiviral response. This work highlights a crucial role for the adaptive immune response in mediating naïve CD4T cell differentiation and cross-protection through epigenetic remodeling for antiviral response against pathogens in an antigen-agnostic manner.