Initiation of Post-Primary Tuberculosis of the Lungs: Exploring the Secret Role of Bone Marrow Derived Stem Cells

Abstract

Mycobacterium tuberculosis (Mtb), the causative organism of pulmonary tuberculosis (PTB) now infects more than half of the world population. The efficient transmission strategy of the pathogen includes first remaining dormant inside the infected host, next undergoing reactivation to cause post-primary tuberculosis of the lungs (PPTBL) and then transmit via aerosol to the community. In this review, we are exploring recent findings on the role of bone marrow (BM) stem cell niche in Mtb dormancy and reactivation that may underlie the mechanisms of PPTBL development. We suggest that pathogen's interaction with the stem cell niche may be relevant in potential inflammation induced PPTBL reactivation, which need significant research attention for the future development of novel preventive and therapeutic strategies for PPTBL, especially in a post COVID-19 pandemic world. Finally, we put forward potential animal models to study the stem cell basis of Mtb dormancy and reactivation.

Keywords: Mycobacterium tuberculosis; altruistic stem cells; bone marrow derived stem cells; dormancy; post-primary tuberculosis of the lungs; reactivation; stem cell niche.

Figure 1

A hypothetical model of MSC mediated PPTBL development. (A) A schematic model of Mtb dormancy and reactivation showing the meaning of different terminologies used in the review article. (B) Hypothetical model showing the role of CD271+BM-MSC in PPTBL development. The model introduces a new self-renewing cell type, the CD271+BM-MSCs as a potential reservoir of dormant Mtb (dMtb). Following primary TB infection, dMtb hide in BM. In adults, inflammation in the lungs mobilizes BM-MSCs. The mobilization process facilitates homing of dMtb harboring BM-MSCs into the lungs leading to PPTBL development [adapted from reference no. (22)].

Figure 2

The emerging role of stem cell altruism in PPTBL development. (A) Inflammation such as acute respiratory tract infection (ARI) in lungs causes mobilization and homing of dMtb harboring BM-MSCs to the lungs. (B) Inside the lungs, dMtb-BM-MSCs self-renew and reprogram from MSCs to altruistic stem cells (ASCs) by the process of stem cell altruism (73, 112, 113). These ASCs undergo clonal proliferation and become permissible for intracellular replication of dMtb. Replicating Mtb exit ASCs into extracellular space to infect alveolar macrophages. During this phase, patient exhibit subclinical exudative, focal pneumonia like phase of PPTBL as shown in chest X-ray of a patient with sub-clinical PPTBL (arrow). (C) A host immune response surrounds the infected alveolar macrophages, and eventually leads to granuloma and cavity formation, thus developing clinical PPTBL as shown in chest X-ray of a PPTBL patient (arrow).

Figure 3

An experimental mouse model of stem cell mediated development of PPTBL. (A) Mouse model of streptomycin dependent mutant 18b-Mtb strain dormancy intracellular to BM-MSCs (22). (B) After 6 months of streptomycin starvation, streptomycin is re-introduced and mice are infected with MHV-1 intranasally to cause acute respiratory tract infection (ARI) inducing BM-MSC mobilization to lungs. (C) The dMtb harboring BM-MSCs in MHV-1 infected lungs expands and reprogram to altruistic stem cells (ASCs; see text) that permit Mtb replication and exit to extracellular space. The reactivated Mtb then infect nearby alveolar macrophages, leading to PPTBL development.