BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

Cirovic, Branko; Bree, L. Charlotte J. de; Groh, Laszlo; Blok, Bastiaan A.; Chan, Jane; Velden, Walter J.F.M. van der; Bremmers, M.E.J.; Crevel, Reinout van; Händler, Kristian; Picelli, Simone; Schulte-Schrepping, Jonas; Klee, Kathrin; Oosting, Marije; Koeken, Valerie A C M; Ingen, Jakko van; Li, Yang; Benn, Christine Stabell; Schultze, Joachim L.; Joosten, Leo A. B.; Curtis, Nigel; Netea, Mihai G.; Schlitzer, Andreas

doi:10.1016/j.chom.2020.05.014

Cited by 289 publications

(282 citation statements)

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“…We also showed previously that hematopoietic stem cell transplantation from β-glucan-trained mice to naive recipients gives rise to increased frequency of neutrophils in the circulation of the latter ( Mitroulis et al., 2018 ). Our findings together with a recent study showing that changes in hematopoietic progenitors and in granulocytes are integral to BCG-induced trained immunity in humans ( Cirovic et al., 2020 ) point to the emerging and hitherto underappreciated role of neutrophils as effectors of trained immunity.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Kalafati

Kourtzelis

Schulte-Schrepping

et al. 2020

Cell

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305

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Summary Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.

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Section: Discussionmentioning

confidence: 99%

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Kalafati

Kourtzelis

Schulte-Schrepping

et al. 2020

Cell

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305

281

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“…Considering that BCG reprograms HSCs toward myelopoiesis and generates protective trained immunity against Mtb ( Cirovic et al., 2020 ; Kaufmann et al., 2018 ), we investigated whether the presence of virulent Mtb in the BM affects innate immunity to infection. Here we show that, although access of Mtb to the BM changes the transcriptional landscape of HSCs and multipotent progenitors (MPPs) similarly to BCG, the magnitude of the IFN-I and heme metabolism pathways significantly differed between BCG and Mtb .…”

Section: Introductionmentioning

confidence: 99%

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

Khan

Downey

Sanz

et al. 2020

Cell

158

151

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Summary 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.

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“…Intravenously delivered BCG can sustainably reprogram murine hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) to enhance myelopoiesis, and the resulting epigenetically modified macrophages and monocytes provided protection against Mtb in vitro and in vivo, respectively [41]. A groundbreaking study demonstrated similar changes in human BM following BCG vaccination in healthy naive subjects, where the upregulated transcriptional shift towards myelopoiesis and subsequent increased cytokine production from PBMCs following nonspecific stimulation was confirmed [40]. Specifically, the epigenetic modifications in HSPCs guarantee continued modification for circulating monocytes 90 days after vaccination (Figure 2).…”

Section: Mechanisms Of Bcg-induced Protective and Trained Immunitymentioning

confidence: 99%

“…BCG responders had distinct methylation patterns at three weeks, and four and eight months post vaccination, which were tied to immune pathways such as "innate immune response" and "leukocyte activation" [26]. Vaccination increased the accessibility of several genes associated with inflammatory processes while decreasing accessibility of genes related to lymphoid development and anti-inflammatory processes [40]. PBMCs from vaccinated subjects demonstrated increased H3K4 trimethylation at promoters for IL-6, TNF, and TLR4 [23].…”

Section: Mechanisms Of Bcg-induced Protective and Trained Immunitymentioning

confidence: 99%

Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Pasco

Anguíta

2020

Cells

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Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

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BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

Cited by 289 publications

References 50 publications

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

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

Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

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