Abstract
Tuberculosis is a leading cause of death due to infections in mankind. The causative pathogen Mycobacterium tuberculosis (Mtb) infects macrophages but also many other mammalian cells including hematopoietic and mesenchymal stem cells (MSCs). MSCs are multipotent and can differentiate into multiple cell phenotypes including macrophage like cells that express scavenger receptor-A (SR-A), mannose receptor, TLR-2/4 and contain NOD1/2 receptors in the cytosol. They express very low levels of HLA-DR (MHC-II) and HLA-ABC (MHC-I) because of which, they can be transplanted without adverse reactions. MSCs have self-renewal and regenerative properties, and secrete cytokines and chemokines; growth factors to reduce inflammation, repair and remodel tissues and maintain homeostasis. Thus, they have been used to treat human diseases including tuberculosis. Mtb infects MSCs from both humans and mice and persists within them for prolonged periods. We illustrate here that naïve MSCs interact with Mtb by phagocytosing them through SR-A, and killing them through intrinsic autophagy and nitric oxide. Persisting organisms then become dormant, and thus MSCs provide a niche for latent tuberculosis. Naive MSCs usually exert immunosuppressive properties on macrophages, T cells and DCs although they can be immune-enhancing depending on environmental milieu, and prior activation with cytokines like IFN-γ. Therefore, MSCs can play a dual role during the pathogenesis of tuberculosis. First, MSCs internalize Mtb either during primary aerosol infection or during progressive disease and migrate to bone marrow, where, they provide a niche, and secrete cytokines to dampen immune cell function. Secondly, they can kill replicating Mtb through autophagy and NO but seem to require additional activation or drugs for complete elimination of dormant Mtb. Since MSCs can be grown in vitro into large numbers for transplantation, and can be either pharmacologically or genetically modified, we discuss emerging stem cell based immunotherapeutic strategies for tuberculosis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Abbreviations
- AM:
-
Alveolar macrophages
- Bcl-2:
-
B cell lymphoma proteins
- EGF:
-
Epithelial growth factor
- FGF-2:
-
Fibroblast growth factor
- HGF:
-
Hepatocyte growth factor
- HLA-DR:
-
Human Leukocyte Antigen–D Related
- HSCs:
-
Hematopoietic stem cells
- IDO:
-
Indoleamine 2,3-Dioxygenase (IDO)
- IGF-1:
-
Insulin-like growth factor-1
- LTBI:
-
Latent tuberculosis Infection
- M1, M2:
-
Macrophage phenotypes
- MDR:
-
Multi drug resistant
- MHC:
-
Major histocompatibility complex
- MNGC:
-
Multinucleate giant cells
- MSCs:
-
Mesenchymal stem cells
- Mtb:
-
Mycobacterium tuberculosis
- NO:
-
Nitric oxide
- NOD-1/2:
-
Nuclear oligomerization domain
- PGE-2:
-
Prostaglandin E2
- ROS:
-
Reactive oxygen species
- SR-A:
-
Scavenger receptor-A
- TGF-α/β:
-
Transforming growth factor-α/β
- TLR:
-
Toll-like receptor
- VEGF:
-
Vascular endothelial growth factor
References
Zumla A, et al. Host-directed therapies for infectious diseases: current status, recent progress, and future prospects. Lancet Infect Dis. 2016;16(4):e47–63.
Baek SH, Li AH, Sassetti CM. Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol. 2011;9(5):e1001065.
Gengenbacher M, Kaufmann SH. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev. 2012;36(3):514–32.
Gomez JE, McKinney JD. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis (Edinb). 2004;84(1–2):29–44.
Wakamoto Y, et al. Dynamic persistence of antibiotic-stressed mycobacteria. Science. 2013;339(6115):91–5.
Frieden TR, et al. Tuberculosis. Lancet. 2003;362(9387):887–99.
Smith I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin Microbiol Rev. 2003;16(3):463–96.
van Crevel R, Ottenhoff TH, van der Meer JW. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002;15(2):294–309.
Saunders BM, Cooper AM. Restraining mycobacteria: role of granulomas in mycobacterial infections. Immunol Cell Biol. 2000;78(4):334–41.
Shaler CR, et al. Pulmonary mycobacterial granuloma increased IL-10 production contributes to establishing a symbiotic host-microbe microenvironment. Am J Pathol. 2011;178(4):1622–34.
Silva Miranda M, et al. The tuberculous granuloma: an unsuccessful host defence mechanism providing a safety shelter for the bacteria? Clin Dev Immunol. 2012;2012:139127.
Flynn JL, et al. Immunology studies in non-human primate models of tuberculosis. Immunol Rev. 2015;264(1):60–73.
Bold TD, Ernst JD. Who benefits from granulomas, mycobacteria or host? Cell. 2009;136(1):17–9.
Russell DG, et al. Foamy macrophages and the progression of the human tuberculosis granuloma. Nat Immunol. 2009;10(9):943–8.
Ramakrishnan L. Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol. 2012;12(5):352–66.
Raghuvanshi S, et al. Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci U S A. 2010;107(50):21653–8.
Das B, et al. CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Sci Transl Med. 2013;5(170):170ra13.
Tornack J, et al. Human and mouse hematopoietic stem cells are a depot for dormant Mycobacterium tuberculosis. PLoS One. 2017;12(1):e0169119.
Lee JH, et al. Anatomically and functionally distinct lung Mesenchymal populations marked by Lgr5 and Lgr6. Cell. 2017;170(6):1149–1163.e12.
Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8(9):726–36.
Ma S, et al. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014;21(2):216–25.
Li X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014;34(3):695–704.
Dominici M, et al. Heterogeneity of multipotent mesenchymal stromal cells: from stromal cells to stem cells and vice versa. Transplantation. 2009;87(9 Suppl):S36–42.
Pal B, Das B. In vitro culture of naive human bone marrow mesenchymal stem cells: a stemness based approach. Front Cell Dev Biol. 2017;5:69.
Park KS, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation. 2010;89(5):509–17.
Khan A, Hunter RL, Jagannath C. Emerging role of mesenchymal stem cells during tuberculosis: the fifth element in cell mediated immunity. Tuberculosis (Edinb). 2016;101S:S45–52.
Kuwana M, et al. Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J Leukoc Biol. 2003;74(5):833–45.
Le Blanc K. Mesenchymal stromal cells: tissue repair and immune modulation. Cytotherapy. 2006;8(6):559–61.
Rasmusson I. Immune modulation by mesenchymal stem cells. Exp Cell Res. 2006;312(12):2169–79.
Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med. 2001;7(6):259–64.
Doorn J, et al. Pro-osteogenic trophic effects by PKA activation in human mesenchymal stromal cells. Biomaterials. 2011;32(26):6089–98.
Chen L, et al. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;3(4):e1886.
Huang X, et al. Three-dimensional co-culture of mesenchymal stromal cells and differentiated osteoblasts on human bio-derived bone scaffolds supports active multi-lineage hematopoiesis in vitro: functional implication of the biomimetic HSC niche. Int J Mol Med. 2016;38(4):1141–51.
Skrahin A, et al. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respir Med. 2014;2(2):108–22.
Parida SK, et al. Cellular therapy in tuberculosis. Int J Infect Dis. 2015;32:32–8.
Skrahin A, et al. Effectiveness of a novel cellular therapy to treat multidrug-resistant tuberculosis. J Clin Tuberc Other Mycobact Dis. 2016;4:21–7.
Yudintceva NM, et al. Application of the allogenic mesenchymal stem cells in the therapy of the bladder tuberculosis. J Tissue Eng Regen Med. 2018;12(3):e1580–93.
Kim HS, et al. Implication of NOD1 and NOD2 for the differentiation of multipotent mesenchymal stem cells derived from human umbilical cord blood. PLoS One. 2010;5(10):e15369.
Khan A, et al. Mesenchymal stem cells internalize Mycobacterium tuberculosis through scavenger receptors and restrict bacterial growth through autophagy. Sci Rep. 2017;7(1):15010.
Yang K, et al. Mesenchymal stem cells detect and defend against gammaherpesvirus infection via the cGAS-STING pathway. Sci Rep. 2015;5:7820.
Rustad KC, Gurtner GC. Mesenchymal stem cells home to sites of injury and inflammation. Adv Wound Care (New Rochelle). 2012;1(4):147–52.
Li Y, et al. Staphylococcus aureus infection of intestinal epithelial cells induces human umbilical cord-derived mesenchymal stem cell migration. Int Immunopharmacol. 2013;15(1):176–81.
Fakhari S, et al. Effect of Helicobacter pylori infection on stromal-derived factor-1/CXCR4 axis in bone marrow-derived mesenchymal stem cells. Adv Biomed Res. 2014;3:19.
Krasnodembskaya A, et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol. 2012;302(10):L1003–13.
Lombardo E, et al. Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J Stem Cells. 2015;7(2):368–79.
Mezey E, Nemeth K. Mesenchymal stem cells and infectious diseases: smarter than drugs. Immunol Lett. 2015;168(2):208–14.
Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles for multipotent, bone marrow-derived stromal cells in host defense. Blood. 2012;119(8):1801–9.
Krasnodembskaya A, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229–38.
Meisel R, et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia. 2011;25(4):648–54.
Brandau S, et al. Mesenchymal stem cells augment the anti-bacterial activity of neutrophil granulocytes. PLoS One. 2014;9(9):e106903.
Raffaghello L, et al. Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells. 2008;26(1):151–62.
Takeda K, et al. Mesenchymal stem cells recruit CCR2(+) monocytes to suppress allergic airway inflammation. J Immunol. 2018;200(4):1261–9.
Lo Sicco C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017;6(3):1018–28.
Nemeth K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15(1):42–9.
Tomioka H, et al. Characteristics of suppressor macrophages induced by mycobacterial and protozoal infections in relation to alternatively activated M2 macrophages. Clin Dev Immunol. 2012;2012:635451.
Abumaree MH, et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Rev. 2013;9(5):620–41.
Liu S, et al. Immune characterization of mesenchymal stem cells in human umbilical cord Wharton’s jelly and derived cartilage cells. Cell Immunol. 2012;278(1–2):35–44.
Liu L, et al. Mesenchymal stem cells ameliorate Th1-induced pre-eclampsia-like symptoms in mice via the suppression of TNF-alpha expression. PLoS One. 2014;9(2):e88036.
Duffy MM, et al. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther. 2011;2(4):34.
Melief SM, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31(9):1980–91.
Glenn JD, et al. Mesenchymal stem cells differentially modulate effector CD8+ T cell subsets and exacerbate experimental autoimmune encephalomyelitis. Stem Cells. 2014;32(10):2744–55.
Carrion F, et al. Opposing effect of mesenchymal stem cells on Th1 and Th17 cell polarization according to the state of CD4+ T cell activation. Immunol Lett. 2011;135(1–2):10–6.
Cao W, et al. Mesenchymal stem cells and adaptive immune responses. Immunol Lett. 2015;168(2):147–53.
Abomaray FM, et al. Human chorionic villous mesenchymal stem cells modify the functions of human dendritic cells, and induce an anti-inflammatory phenotype in CD1+ dendritic cells. Stem Cell Rev. 2015;11(3):423–41.
de Oliveira Bravo M, Carvalho JL, Saldanha-Araujo F. Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression. Purinergic Signal. 2016;12(4):595–609.
Peters W, et al. Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2001;98(14):7958–63.
Ernst JD. Mechanisms of M. tuberculosis immune evasion as challenges to TB vaccine design. Cell Host Microbe. 2018;24(1):34–42.
Voskuil MI, et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med. 2003;198(5):705–13.
Naik SK, et al. Mouse bone marrow Sca-1(+) CD44(+) mesenchymal stem cells kill avirulent mycobacteria but not Mycobacterium tuberculosis through modulation of cathelicidin expression via the p38 mitogen-activated protein kinase-dependent pathway. Infect Immun. 2017;85(10):e00471-17.
Bonilla DL, et al. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity. 2013;39(3):537–47.
Yang K, et al. Macrophage-mediated inflammatory response decreases mycobacterial survival in mouse MSCs by augmenting NO production. Sci Rep. 2016;6:27326.
Garhyan J, et al. Preclinical and clinical evidence of Mycobacterium tuberculosis persistence in the hypoxic niche of bone marrow mesenchymal stem cells after therapy. Am J Pathol. 2015;185(7):1924–34.
Rehman J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–8.
Liu GY, et al. ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. Acta Pharmacol Sin. 2015;36(12):1473–9.
Beamer G, et al. Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis that survive antibiotic treatment. Am J Pathol. 2014;184(12):3170–5.
Lopes CS, et al. CD271+ Mesenchymal stem cells as a possible infectious niche for leishmania infantum. PLoS One. 2016;11(9):e0162927.
Jacobs SA, et al. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013;91(1):32–9.
Noone C, et al. IFN-gamma stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev. 2013;22(22):3003–14.
Sinclair KA, et al. Mesenchymal stromal cells are readily recoverable from lung tissue, but not the alveolar space, in healthy humans. Stem Cells. 2016;34(10):2548–58.
Lee ST, et al. Effect of mesenchymal stem cell transplantation on the engraftment of human hematopoietic stem cells and leukemic cells in mice model. Int J Hematol. 2008;87(3):327–37.
Bensidhoum M, et al. Homing of in vitro expanded Stro-1- or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment. Blood. 2004;103(9):3313–9.
Fu X, et al. Comparison of immunological characteristics of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Tissue Eng Part A. 2015;21(3–4):616–26.
Ding DC, et al. Characterization of HLA-G and related immunosuppressive effects in human umbilical cord stroma-derived stem cells. Cell Transplant. 2016;25(2):217–28.
Feng CG, et al. Interferon-inducible immunity-related GTPase Irgm1 regulates IFN gamma-dependent host defense, lymphocyte survival and autophagy. Autophagy. 2009;5(2):232–4.
Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994;78(6):915–8.
Wallis RS, et al. Tuberculosis--advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers. Lancet Infect Dis. 2016;16(4):e34–46.
Erokhin VV, et al. Systemic transplantation of autologous mesenchymal stem cells of the bone marrow in the treatment of patients with multidrug-resistant pulmonary tuberculosis. Probl Tuberk Bolezn Legk. 2008;(10):3–6.
Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22.
Giuliani M, et al. TLR ligands stimulation protects MSC from NK killing. Stem Cells. 2014;32(1):290–300.
Yu B, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol. 2015;182:349–60.
Schwartz YS, et al. BCG infection in mice is promoted by naive mesenchymal stromal cells (MSC) and suppressed by poly(A:U)-conditioned MSC. Tuberculosis (Edinb). 2016;101:130–6.
Sioud M, et al. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand J Immunol. 2010;71(4):267–74.
Mahon RN, Hafner R. Immune cell regulatory pathways unexplored as host-directed therapeutic targets for Mycobacterium tuberculosis: an opportunity to apply precision medicine innovations to infectious diseases. Clin Infect Dis. 2015;61Suppl 3:S200–16.
Singh P, Subbian S. Harnessing the mTOR pathway for tuberculosis treatment. Front Microbiol. 2018;9:70.
Tomchuck SL, et al. Mesenchymal stem cells as a novel vaccine platform. Front Cell Infect Microbiol. 2012;2:140.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Khan, A., Jagannath, C. (2019). Interactions of Mycobacterium tuberculosis with Human Mesenchymal Stem Cells. In: Cirillo, J., Kong, Y. (eds) Tuberculosis Host-Pathogen Interactions. Springer, Cham. https://doi.org/10.1007/978-3-030-25381-3_5
Download citation
DOI: https://doi.org/10.1007/978-3-030-25381-3_5
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-25380-6
Online ISBN: 978-3-030-25381-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)