Severe persistent mycobacteria antigen stimulation causes lymphopenia through impairing hematopoiesis

Front Cell Infect Microbiol. 2023 Jan 18:13:1079774. doi: 10.3389/fcimb.2023.1079774. eCollection 2023.

Abstract

Miliary tubersculosis (TB), an acute systemic blood disseminated tuberculosis mainly caused by Mycobacterium tuberculosis (M. tuberculosis), can cause signs of lymphopenia in clinical patients. To investigate whether/how persistent mycobacteria antigen stimulation impairs hematopoiesis and the therapeutic effect of interleukin-7 (IL-7), a mouse model of Mycobacterium Bovis Bacillus Calmette-Guérin (BCG) intravenous infection with/without an additional stimulation with M. tuberculosis multi-antigen cocktail containing ESAT6-CFP10 (EC) and Mtb10.4-HspX (MH) was established. Consistent with what happened in miliary TB, high dose of BCG intravenous infection with/without additional antigen stimulation caused lymphopenia in peripheral blood. In which, the levels of cytokines IFN-γ and TNF-α in serum increased, and consequently the expression levels of transcription factors Batf2 and IRF8 involved in myeloid differentiation were up-regulated, while the expression levels of transcription factors GATA2 and NOTCH1 involved in lymphoid commitment were down-regulated, and the proliferating activity of bone marrow (BM) lineage- c-Kit+ (LK) cells decreased. Furthermore, recombinant Adeno-Associated Virus 2-mediated IL-7 (rAAV2-IL-7) treatment could significantly promote the elevation of BM lymphoid progenitors. It suggests that persistent mycobacteria antigen stimulation impaired lymphopoiesis of BM hematopoiesis, which could be restored by complement of IL-7.

Keywords: BCG; IL-7; hematopoiesis; lymphopenia; miliary tuberculosis; mycobacterium tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial
  • BCG Vaccine
  • Hematopoiesis
  • Interleukin-7
  • Lymphopenia*
  • Mice
  • Mycobacterium bovis*
  • Mycobacterium tuberculosis*
  • Transcription Factors
  • Tuberculosis*

Substances

  • Antigens, Bacterial
  • Interleukin-7
  • BCG Vaccine
  • Transcription Factors

Grants and funding

This work was funded by National Key Research and Development Program of China (2021YFC2301503), Youth Science Fund Project of the National Natural Science Foundation of China (82001675), the Fundamental Research Funds for the Central Universities of the Lanzhou University (lzujbky-2021-4), and Gansu Science and Technology Project of China (21JR7RA534).