Cracking the stem cells' code in vaccination against TB
Final Report Abstract
My research project entitled “Cracking the stem cells’ code in vaccination against TB” was focused on the effect of BCG vaccination on Hematopoietic Stem Cells (HSCs) and the initiation of trained innate immunity against Mycobacterium tuberculosis (Mtb) infection. Globally, Tuberculosis (TB) is still a major cause of death that kills 1.6 million people every year. The only licensed vaccine, Bacille Calmette Guérin (BCG), is intradermally administered to 80% of the annual birth cohort, but only protects against severe forms of TB in early childhood. This underscores the urgent need for a better understanding of TB pathogenesis to employ novel and innovative approaches that will prevent disease. Interestingly, it has recently been shown that BCG can confer resistance to heterologous secondary infections by epigenetic reprogramming of monocytes and altering the cell metabolism. Considering the nature of monocyte/macrophage differentiation, as well as their relatively short lifespan, it is unknown how these cells transmit their memory phenotype to their progeny and provide sustained protection. Thus, vaccine strategies targeting monocyte/macrophages have limited efficacy for generating long-term innate immune memory. In contrast to monocytes/macrophages, their progenitor cells, the HSCs, are long-lived cells that reside in the BM. We therefore hypothesized that in contrast to the lungs, the BM is actually the critical site of immune protection as well as evasion in TB. We aimed at investigating the changes in HSC expansion and gene transcription by virulent Mtb infection and BCG vaccination. In this project, we have shown that intravenous BCG vaccination (BCG-iv), in contrast to subcutaneous BCG vaccination (BCG-sc), significantly expands the LKS (Lineage-negative, c-Kitpositive, Sca-1-positive) population that contains the HSCs as well as multipotent progenitors (MPPs). This increase in the percentage and total cell number of LKS cells in the BM was mainly due to an increased number of short-term HSCs (CD150+ CD48+) and MPPs (CD150- CD48+) that leads to increased numbers of myeloid progenitors (MPP3, CD34+ Flt3-). Alongside this expansion, the BCG-iv vaccination reprograms HSCs at the epigenetic and transcriptional level. Importantly, the transcriptional signatures of HSCs from BCG-iv vaccinated mice were transmitted to the macrophages derived from the BM (BMDMs), and BMDMs provided protection against virulent Mtb challenge. These data indicate that access of BCG into the BM reprograms HSCs specifically to generate a protective trained immunity against subsequent pulmonary Mtb infection. To investigate whether the protective impact of systemic BCG (iv) vaccination was transmitted from HSCs to monocytes to macrophages in vivo, we implicated three different mouse models. First, by using bone marrow chimeric mice, we showed that transplantation of HSCs from BCG-iv vaccinated mice provides protection against Mtb infection. Second, by using parabiosis we demonstrated that monocytes derived from the BM of BCG-iv vaccinated mice provided protection against Mtb infection. Third, by using an adoptive transfer model, we showed that adoptive transfer of BMDMs from BCG-iv vaccinated mice generated significant protection against Mtb infection. Finally, we demonstrated that BCG-induced reprogramming of HSCs and generation of protective trained immunity was mediated by IFN-gamma signaling. Currently, we are investigating the potential contribution of BCG for generating HSC-mediated trained immunity in humans using both an in vitro model of human HSCs as well as a humanized mouse model.
Publications
- (2020) M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Cell 183 (3) 752-770.e22
Khan, Nargis; Downey, Jeffrey; Sanz, Joaquin; Kaufmann, Eva; Blankenhaus, Birte; Pacis, Alain; Pernet, Erwan; Ahmed, Eisha; Cardoso, Silvia; Nijnik, Anastasia; Mazer, Bruce; Sassetti, Christopher; Behr, Marcel A.; Soares, Miguel P.; Barreiro, Luis B.; Div
(See online at https://doi.org/10.1016/j.cell.2020.09.062) - (2020) NK cell recruitment limits tissue damage during an enteric helminth infection. Mucosal immunology 13 (2) 357–370
Gentile, Maria E.; Li, Yue; Robertson, Amicha; Shah, Kathleen; Fontes, Ghislaine; Kaufmann, Eva; Polese, Barbara; Khan, Nargis; Parisien, Marc; Munter, Hans M.; Mandl, Judith N.; Diatchenko, Luda; Divangahi, Maziar; King, Irah L.
(See online at https://doi.org/10.1038/s41385-019-0231-8) - (2020) β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1. Cell reports 31 (7) 107634
Moorlag, Simone J. C. F. M.; Khan, Nargis; Novakovic, Boris; Kaufmann, Eva; Jansen, Trees; van Crevel, Reinout; Divangahi, Maziar; Netea, Mihai G.
(See online at https://doi.org/10.1016/j.celrep.2020.107634) - (2017) Unravelling the networks dictating host resistance versus tolerance during pulmonary infections. Cell Tissue Res. 367:525–536
Meunier I and Kaufmann E, Downey J, Divangahi M
(See online at https://doi.org/10.1007/s00441-017-2572-5) - (2018) BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell 172:176–190
Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonca LE, Pacis A, Tzelepis F, Pernet E, Dumaine A, Grenier JC, Mailhot-Léonard F, Ahmed E, Belle J, Besla R, Mazer B, King IL, Nijnik A, Robbins CS, Barreiro LB, Divangahi M
(See online at https://doi.org/10.1016/j.cell.2017.12.031) - (2018) Beyond Killing Mycobacterium tuberculosis: Disease Tolerance. Front. Immunol. 9:2976
Divangahi M, Khan N, Kaufmann E
(See online at https://doi.org/10.3389/fimmu.2018.02976)
