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

J Infect Dis. 2021 Dec 1;224(11):1962-1972. doi: 10.1093/infdis/jiab235.

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.

Keywords: MDSCs; diphtheria fusion protein toxin; host-directed therapy; immunotherapy; tuberculosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diphtheria Toxin / therapeutic use*
  • Disease Models, Animal
  • Immunotherapy / methods*
  • Mice
  • Mycobacterium tuberculosis / immunology*
  • Myeloid-Derived Suppressor Cells / immunology*
  • Recombinant Fusion Proteins / therapeutic use
  • T-Lymphocytes
  • Tuberculosis / therapy*

Substances

  • Diphtheria Toxin
  • Recombinant Fusion Proteins