SOCS1 antagonist-expressing recombinant BCG enhances anti-tuberculosis protection in a mouse model

Abstract Suppressor of cytokine signaling 1 (SOCS1) plays a key role in the negative regulation of JAK/STAT signaling, which is involved in innate immunity and subsequent adaptive immunity. Bacillus Calmette-Guerin (BCG) induces up-regulation of SOCS1 expression in host cells, which may lead to the suppression of immune responses by BCG via inhibition of the JAK/STAT signaling pathway. This might cause reduction in the protective effect of a BCG vaccine. In the present study, we assessed the immune responses and protective efficacy of a recombinant BCG vaccine expressing an SOCS1 antagonist molecule (rBCG-SOCS1DN). C57BL/6 mice were immunized with rBCG-SOCS1DN or parental BCG Tokyo vaccine strain harboring an empty plasmid vector (rBCG-pSO). rBCG-SOCS1DN enhanced induction bone marrow-derived dendritic cell activation and T cells activation compared to rBCG-pSO. The amount of IFN-g, TNF-a and IL-6 produced by splenocytes of rBCG-SOCS1DN-immunized mice were larger than those produced by splenocytes of rBCG-pSO-immunized mice. Moreover, the rBCG-SOCS1DN-immunized mice showed a substantial reduction in the number of colony-forming units (CFU) of Mycobacterium tuberculosis (Mtb) in the lungs and spleens in comparison with that in control BCG-immunized mice when the immunized mice were infected with a highly pathogenic Mtb strain by inhalation. These findings provide evidence for the possibility of rBCG-SOCS1DN being an effective Mtb vaccine with a novel concept of rBCG as a tool for immunomodulation in host cells.