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

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.

Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

“…Although TB is commonly considered a pulmonary disease, M. tuberculosis can infect many organs. In mice and humans, the BM can serve as bacterial niche during latent TB infection with mesenchymal stem cells and long-term HSCs providing a cellular reservoir for M. tuberculosis (Garhyan et al, 2015;Tornack et al, 2017). It is likely that TB per se, but particularly bacilli within HSCs, cause epigenetic changes that impact their genetic expression programs.…”

Guidelines for the use of flow cytometry and cell sorting in immunological studies*

“…Phenotypic characterization of human pHSCs in the peripheral blood in vivo. LT‐pHSCs were identified as Lin – CD34 + CD38 – CD90 + cells, and MPPs as Lin – CD34 + CD38 + CD90 − cells .…”

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

“…Recent studies in mice have shown that intradermally injected Mtb are asymptomatically contained in the draining lymph node for an extended period of time and have used this approach to model LTBI in humans with the goal of understanding failure of containment arising from immune suppression 19,20 . Because the LTBI mouse model shares many features of latent TB in humans, we hypothesize that it reflects at least a portion of the disease spectrum.…”