Hematopoietic stem cells as a niche for Mycobacterium tuberculosis

Abstract

Hematopoietic stem cells (HSCs) play an indispensable role in maintaining immune competence through their differentiation into mature lymphoid and myeloid effector cells. The manipulation of the hematopoietic system by infectious agents can, therefore, significantly disrupt protective immune function, facilitating pathogen persistence and exacerbating disease. M. tuberculosis is a paradigm of pathogen persistence. The recent discovery of mycobacterial DNA within HSCs introduced a potential yet undefined strategy by which M. tuberculosis may subvert host immunity by directly targeting the source of immune cell generation. The hallmarks of this work were to characterize how otherwise non-permissive cells, namely the HSCs, internalize M. tuberculosis and to identify the underlying pathways. We identified CD36 as the potential surface receptor recognizing M. tuberculosis and showed internalization to involve macropinocytosis-independent membrane ruffling instead of canonical phagocytosis pathways and discovered a yet-to-be elucidated involvement of clathrin interactions. Further, the heterogeneity among immunophenotypically defined HSCs indiciated inflammaging-related effects to promote permissiveness to infection by M. tuberculosis. Identifying the pathways exploited by M. tuberculosis for internalization and delineating the signals that drive HSC susceptibility may help to uncover novel targets for host-directed therapies aimed at protecting these crucial cells against infection and restoring host immune competence.