Human and Mouse Hematopoietic Stem Cells Are a Depot for Dormant Mycobacterium tuberculosis

PLoS One. 2017 Jan 3;12(1):e0169119. doi: 10.1371/journal.pone.0169119. eCollection 2017.

Abstract

An estimated third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), with no clinical signs of tuberculosis (TB), but lifelong risk of reactivation to active disease. The niches of persisting bacteria during latent TB infection remain unclear. We detect Mtb DNA in peripheral blood selectively in long-term repopulating pluripotent hematopoietic stem cells (LT-pHSCs) as well as in mesenchymal stem cells from latently infected human donors. In mice infected with low numbers of Mtb, that do not develop active disease we, again, find LT-pHSCs selectively infected with Mtb. In human and mouse LT-pHSCs Mtb are stressed or dormant, non-replicating bacteria. Intratracheal injection of Mtb-infected human and mouse LT-pHSCs into immune-deficient mice resuscitates Mtb to replicating bacteria within the lung, accompanied by signs of active infection. We conclude that LT-pHSCs, together with MSCs of Mtb-infected humans and mice serve as a hitherto unappreciated quiescent cellular depot for Mtb during latent TB infection.

MeSH terms

  • Adult
  • Animals
  • Antigens, CD34 / metabolism
  • Bone Marrow Cells / metabolism
  • Cell Separation
  • Female
  • Flow Cytometry
  • Hematopoietic Stem Cells / microbiology*
  • Humans
  • Latent Tuberculosis / microbiology*
  • Lung / microbiology
  • Male
  • Mesenchymal Stem Cells / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mycobacterium tuberculosis*
  • Signaling Lymphocytic Activation Molecule Family Member 1 / metabolism
  • Young Adult

Substances

  • Antigens, CD34
  • Slamf1 protein, mouse
  • Signaling Lymphocytic Activation Molecule Family Member 1

Grant support

This work was supported by the European Union’s Seventh Framework Programme (EU FP7) project “ADITEC” (HEALTH-F4-2011-280873); and EU Horizon 2020 project “TBVAC 2020” (grant 643381) to SHEK. In addition, the work was supported in parts by a Reinhard Koselleck-Grant of the Deutsche Forschungsgemeinschaft ME 2764/1-1 to FM.