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.
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•Access of BCG to the bone marrow expands HSCs and promotes myelopoiesis•BCG educates HSCs to generate trained monocytes/macrophages•BCG induces a unique epigenetic and transcriptomic signature in macrophages•BCG-trained macrophages are highly protective against pulmonary M. tuberculosis infection
BCG induces trained immunity through education of hematopoietic stem cells.
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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•BCG and Mtb uniquely reprogram HSCs for at least 1 year•Mtb suppresses myelopoiesis and impairs HSC engraftment•Mtb hijacks a type I IFN/iron axis to induce necroptosis specifically in myeloid lineage•Reprogramming of HSCs by a type I IFN/iron axis impairs trained immunity
The pathogen Mycobacterium tuberculosis reprograms hematopoietic stem cells and limits myelopoiesis while impairing trained immunity responses via a type I IFN/iron signaling axis.
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.
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•β-glucan induces protective trained immunity in human monocytes infected with Mtb•β-glucan induces protective trained immunity in mice infected with Mtb•β-glucan-mediated protection against Mtb is dependent on IL-1 signaling•β-glucan increases expansion of hematopoietic progenitors and myelopoiesis via IL-1
Moorlag et al. show that β-glucan induces protective trained immunity in human monocytes and in mice infected with virulent Mtb. β-glucan-mediated protection against Mtb is dependent on IL-1 signaling and is associated with the expansion of hematopoietic stem and progenitor cells in the bone marrow and increased myelopoiesis.
Host defense strategies against infectious diseases are comprised of both host resistance and disease tolerance. Resistance is the ability of the host to prevent invasion or to eliminate the ...pathogen, while disease tolerance is defined by limiting the collateral tissue damage caused by the pathogen and/or the immune response without exerting direct effects on pathogen growth. Our incomplete understanding of host immunity against tuberculosis (TB) is predominately rooted in our bias toward investigating host resistance. Thus, we must refocus our efforts to understand the entire spectrum of immunity against
to control TB.
Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. We ...postulate that an evolutionarily ancient protective mechanism against infection, known as trained immunity, drives pathological inflammation in DMD. Here we show that bone marrow-derived macrophages from a murine model of DMD (mdx) exhibit cardinal features of trained immunity, consisting of transcriptional hyperresponsiveness associated with metabolic and epigenetic remodeling. The hyperresponsive phenotype is transmissible by bone marrow transplantation to previously healthy mice and persists for up to 11 weeks post-transplant. Mechanistically, training is induced by muscle extract in vitro. The functional and epigenetic changes in bone marrow-derived macrophages from dystrophic mice are TLR4-dependent. Adoptive transfer experiments further support the TLR4-dependence of trained macrophages homing to damaged muscles from the bone marrow. Collectively, this suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD.
The diaphragm is a unique skeletal muscle due to its continuous activation pattern during the act of breathing. The ontogeny of macrophages, pivotal cells for skeletal muscle maintenance and ...regeneration, is primarily based on two distinct origins: postnatal bone marrow-derived monocytes and prenatal embryonic progenitors. Here we employed chimeric mice to study the dynamics of these two macrophage populations under different conditions. Traditional chimeric mice generated through whole body irradiation showed virtually complete elimination of the original tissue-resident macrophage pool. We then developed a novel method which employs lead shielding to protect the diaphragm tissue niche from irradiation. This allowed us to determine that up to almost half of tissue-resident macrophages in the diaphragm can be maintained independently from bone marrow-derived monocytes under steady-state conditions. These findings were confirmed by long-term (5 months) parabiosis experiments. Acute diaphragm injury shifted the macrophage balance toward an overwhelming predominance of bone marrow (monocyte)-derived macrophages. However, there was a remarkable reversion to the pre-injury ontological landscape after diaphragm muscle recovery. This diaphragm shielding method permits analysis of the dynamics of macrophage origin and corresponding function under different physiological and pathological conditions. It may be especially useful for studying diseases which are characterized by acute or chronic injury of the diaphragm and accompanying inflammation.
Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch ...of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism.
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•BCG vaccination provides significant protection against IAV in mice and hamsters•BCG provides no protection against SARS-CoV-2 in mice and hamsters•SARS-CoV-2 induces pulmonary hemorrhage and disseminates to the bone marrow•Monocytes from BCG-vaccinated humans induce more cytokines to IAV than SARS-CoV-2
Kaufmann et al. show that BCG vaccination protects mice and hamsters against influenza, but not SARS-CoV-2. The distinct tropism of SARS-CoV-2 for pulmonary endothelial cells may lead to lung hemorrhage and systemic viral dissemination. Thus, the protection of BCG against viral pathogens is mainly determined by pathogenesis of infections.
Obesity is known to increase the complications of the COVID-19 coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the exact mechanisms of SARS-CoV-2 ...infection in obese patients have not been clearly elucidated. This study aims to better understand the effect of obesity on the course of SARS-CoV-2 infection and identify candidate molecular pathways involved in the progression of the disease, using an in vitro live infection model and RNA sequencing. Results from this study revealed the enhancement of viral load and replication in bronchial epithelial cells (NHBE) from obese subjects at 24 h of infection (MOI = 0.5) as compared to non-obese subjects. Transcriptomic profiling via RNA-Seq highlighted the enrichment of lipid metabolism-related pathways along with
, an inflammasome regulator, as a unique differentially expressed gene (DEG) in infected bronchial epithelial cells from obese subjects. Such findings correlated with altered cytokine and angiotensin-converting enzyme-2 (ACE2) expression during infection of bronchial cells. These findings provide a novel insight on the molecular interplay between obesity and SARS-CoV-2 infection. In conclusion, this study demonstrates the increased SARS-CoV-2 infection of bronchial epithelial cells from obese subjects and highlights the impaired immunity which may explain the increased severity among obese COVID-19 patients.
Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a ...virulent strain of
(H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for
survival and that metabolic reprogramming may be a viable host targeted therapy against TB.
Parasitic helminths cause significant damage as they migrate through host tissues to complete their life cycle. While chronic helminth infections are characterized by a well-described Type 2 immune ...response, the early, tissue-invasive stages are not well understood. Here we investigate the immune pathways activated during the early stages of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm of mice. In contrast to the Type 2 immune response present at later stages of infection, a robust Type 1 immune signature including IFNg production was dominant at the time of parasite invasion and granuloma formation. This early response was associated with an accumulation of activated Natural Killer (NK) cells, with no increase of other innate lymphoid cell populations. Parabiosis and confocal microscopy studies indicated that NK cells were recruited from circulation to the small intestine, where they surrounded parasitic larvae. NK cell recruitment required IFNγ receptor signaling, but was independent of CXCR3 expression. The depletion of tissue-infiltrating NK cells altered neither worm burden nor parasite fitness, but increased vascular injury, suggesting a role for NK cells in mediating tissue protection. Together, these data identify an unexpected role for NK cells in promoting disease tolerance during the invasive stage of an enteric helminth infection.
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