Effective Host-Directed Therapy for Tuberculosis by Depletion of Myeloid-Derived Suppressor Cells and Related Cells Using a Diphtheria Toxin Fusion Protein

Abstract Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in tuberculosis patients and have been found to be permissive for Mycobacterium tuberculosis proliferation. To determine whether depletion of MDSCs may improve host control of tuberculosis, we used a novel diphtheria t...

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Bibliographic Details
Published in:The Journal of infectious diseases 2021-12, Vol.224 (11), p.1962-1972
Main Authors: Parveen, Sadiya, Lun, Shichun, Urbanowski, Michael E, Cardin, Mitchell, Shen, Jessica, Murphy, John R, Bishai, William R
Format: Article
Language:English
Subjects:
Animals
Cell fusion
Diphtheria
Diphtheria toxin
Diphtheria Toxin - therapeutic use
Disease Models, Animal
Fusion protein
Immunotherapy
Immunotherapy - methods
Interleukin 4
Lymphocytes T
Major and Brief Reports
Mice
Monocytes
Mycobacterium tuberculosis - immunology
Myeloid-Derived Suppressor Cells - immunology
Recombinant Fusion Proteins - therapeutic use
Suppressor cells
T-Lymphocytes
Tuberculosis
Tuberculosis - therapy
γ-Interferon
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Summary:Abstract Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in tuberculosis patients and have been found to be permissive for Mycobacterium tuberculosis proliferation. To determine whether depletion of MDSCs may improve host control of tuberculosis, we used a novel diphtheria toxin-based fusion protein DABIL-4 that targets and depletes interleukin 4 (IL-4) receptor-positive cells. We show that DABIL-4 depletes both polymorphonuclear MDSCs and monocytic MDSCs, increases interferon-γ + T cells, and reduces the lung bacillary burden in a mouse tuberculosis model. These results indicate that MDSC-depleting therapies targeting the IL-4 receptor are beneficial in tuberculosis and offer an avenue towards host-directed tuberculosis therapy. Our study demonstrates that the diphtheria fusion toxin protein DABIL-4 depletes immunosuppressive cell populations, including MDSCs and M2 macrophages, thereby potentiating the recruitment and cytotoxic functions of the effector T cells resulting in better clearance of Mycobacterium tuberculosis in murine lungs.
ISSN:0022-1899
1537-6613
DOI:10.1093/infdis/jiab235