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J Immunol. 2019 May 17. pii: ji1800694. doi: 10.4049/jimmunol.1800694. [Epub ahead of print]

SOCS1 Antagonist-Expressing Recombinant Bacillus Calmette-Guérin Enhances Antituberculosis Protection in a Mouse Model.

Author information

1
Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
2
Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Ibaraki 305-0843, Japan.
3
Research and Development Department, Japan BCG Laboratory, Kiyose, Tokyo 204-0022, Japan; and.
4
Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.
5
Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; yasutomi@nibiohn.go.jp.

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-Guérin (BCG) induces upregulation 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 A reduction in the protective effect of a BCG vaccine. In the current study, we assessed the immune responses to and the protective efficacy of a recombinant BCG secreting a dominant negative mutant of the SOCS1 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 the activation of bone marrow-derived dendritic cells and the activation of T cells compared with those with rBCG-pSO. The amounts of IFN-γ, TNF-α, 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 CFU of Mycobacterium tuberculosis in the lungs and spleens compared with that in control BCG-immunized mice when the immunized mice were infected with a highly pathogenic M. tuberculosis strain by inhalation. These findings provide evidence for the possibility of rBCG-SOCS1DN being an effective M. tuberculosis vaccine with a novel concept of rBCG as a tool for immunomodulation in host cells.

PMID:
31101668
DOI:
10.4049/jimmunol.1800694

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