M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

Khan N ，Downey J ，Sanz J ，Kaufmann E ，Blankenhaus B ，Pacis A ，Pernet E ，Ahmed E ，Cardoso S ，Nijnik A ，Mazer B ，Sassetti C ，Behr MA ，Soares MP ，Barreiro LB ，Divangahi M ... -  《-》

Infection with hypervirulent Mycobacterium tuberculosis triggers emergency myelopoiesis but not trained immunity.

During infection, bone marrow (BM) hematopoiesis is reprogrammed toward myeloid cell production, a mechanism named emergency myelopoiesis. In addition to replenishing myeloid cells, emergency myelopoiesis has been linked to trained immunity, a process that allows enhanced innate immune responses to secondary challenges. Although hematopoietic alterations during tuberculosis (TB) have been described and Mycobacterium tuberculosis may colonize the BM, studies using the mouse model of infection and the laboratory reference strain M. tuberculosis H37Rv have demonstrated limited emergency myelopoiesis and trained immunity. To further address this issue, we aerosol- infected C57BL/6 mice with high doses of the hypervirulent M. tuberculosis isolate HN878 and monitored alterations to the BM. This experimental model better resembles the human blood immune signature of TB. We found increased frequencies of lineage-Sca-1+cKit+ (LSK) cells and the granulocyte/macrophage progenitor (GMP) population. At the mature cell level, we observed an increase of monocytes and neutrophils in the blood and lung, likely reflecting the increased BM myeloid output. Monocytes or monocyte-derived macrophages recovered from the BM of M. tuberculosis HN878-infected mice did not show signs of trained immunity, suggesting an uncoupling of emergency myelopoiesis and trained immunity in the BM. Surprisingly, M. tuberculosis HN878-induced emergency myelopoiesis was not fully dependent on IFNγ, as mice lacking this cytokine and infected under the same conditions as wild-type mice still presented BM alterations. These data expand our understanding of the immune response to M. tuberculosis and raise awareness of pathogen strain-imposed differences to host responses.

Maceiras AR ，Silvério D ，Gonçalves R ，Cardoso MS ，Saraiva M ... -  《-》

β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1.

β-glucan is a potent inducer of epigenetic and functional reprogramming of innate immune cells, a process called "trained immunity," resulting in an enhanced host response against secondary infections. We investigate whether β-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection. β-glucan induces trained immunity via histone modifications at gene promoters in human monocytes, which is accompanied by the enhanced production of proinflammatory cytokines upon secondary Mtb challenge and inhibition of Mtb growth. Mice treated with β-glucan are significantly protected against pulmonary Mtb infection, which is associated with the expansion of hematopoietic stem and progenitor cells in the bone marrow and increased myelopoiesis. The protective signature of β-glucan is mediated via IL-1 signaling, as β-glucan shows no protection in mice lacking a functional IL-1 receptor (IL1R-/-). The administration of β-glucan may be used as a novel strategy in the treatment of mycobacterial infections and possibly as an adjuvant to improve anti-tuberculosis vaccines.

Moorlag SJCFM ，Khan N ，Novakovic B ，Kaufmann E ，Jansen T ，van Crevel R ，Divangahi M ，Netea MG ... -  《-》

BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis.

The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.

Kaufmann E ，Sanz J ，Dunn JL ，Khan N ，Mendonça 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 ... -  《-》

Natural and trained innate immunity against Mycobacterium tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains a major global health emergency. It is estimated that one third of global population are affected, predominantly with latent granuloma form of the disease. Mtb co-evolved with humans, for its obligatory intra-macrophage phagosome habitat and slow replication, balanced against unique mycobacterial innate immunity, which appears to be highly complex. TB is transmitted via cough aerosol Mtb inhalation. Bovine TB attenuated Bacillus Calmette Guerin (BCG) live vaccine has been in practice for protection of young children from severe disseminated Mtb infection, but not sufficiently for their lungs, as obtained by trials in TB endemic community. To augment BCG vaccine-driven innate and adaptive immunity for neonates and better protection against adult pulmonary TB, a number of BCG pre-vaccination based, subset vaccine candidates have been tested via animal preclinical, followed by safe clinical trials. BCG also enhances innate macrophage trained immunity and memory, through primordial intracellular Toll-like receptors (TLRs) 7 and 9, which recognise distinct mycobacterial molecular pattern signature. This signature is transmitted by TLR signalling via nuclear factor-κB, for activating innate immune transcription and expression of gene profiling in a mycobacterial signature-specific manner. These are epigenetically imprinted in reprogramming of distinct chromatin areas for innate immune memory, to be recalled following lung reinfection. Unique TB innate immunity and its trained memory are considered independent from adaptive immune B and T cells. On the other hand, adaptive immunity is crucial in Mtb containment in granulomatous latency, supported by innate immune cell infiltration. In nearly 5-10 % of susceptible people, latent TB may be activated due to immune evasion by Mtb from intracellular phagosome within macrophage, perpetrating TB. However, BCG and new recombinant BCG vaccines have the capacity, as indicated in pre- and clinical trials, to overcome such Mtb evasion. Various strategies include pro-inflammatory-bactericidal type 1 polarisation (M1) phenotype of the infected macrophage, involving thrombospondin-TLR pathway. Saprophytic M. smegmatis-based recombinant vaccines are also promising candidates against TB. BCG vaccination of neonates/infants in TB endemic countries also reduced their pneumonia caused by various microbes independent of TB immunity. Here, we discuss host immune response against Mtb, its immune evasion strategies, and the important role innate immunity plays in the development of protection against TB.

Ferluga J ，Yasmin H ，Al-Ahdal MN ，Bhakta S ，Kishore U ... -  《-》