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GM-CSF Programs Hematopoietic Stem and Progenitor Cells During Candida albicans Vaccination for Protection Against Reinfection.

ABSTRACT: More mechanistic studies are needed to reveal the hidden details of in vivo-induced trained immunity. Here, using a Candida albicans live vaccine mouse model we show that vaccination protects mice against a secondary infection and increases the number of bone marrow, and especially, splenic trained monocytes. Moreover, vaccination expands and reprograms hematopoietic stem and progenitor cells (HSPCs) early during infection and mobilize them transiently to the spleen to produce trained macrophages. Trained HSPCs are not only primed for myeloid cell production but also reprogramed to produce a greater amount of proinflammatory cytokines in response to a second challenge. Additionally, their adoptive transfer is sufficient to protect mice against reinfection. Mechanistically, autocrine GM-CSF activation of HSPCs is responsible for the trained phenotype and essential for the vaccine-induced protection. Our findings reveal a fundamental role for HSPCs in the trained immune protective response, opening new avenues for disease prevention and treatment.

SUBMITTER: Bono C

PROVIDER: S-EPMC8715000 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Autocrine GM-CSF signaling programs hematopoietic stem and progenitor cells during Candida albicans infection for protection against reinfection

Project description:More mechanistic studies are needed to reveal the hidden details of in vivo-induced trained immunity. Here, using a Candida albicans live vaccine mouse model we show that vaccination protects mice against a secondary infection and increases the number of bone marrow, and especially, splenic trained monocytes. Moreover, vaccination reprograms hematopoietic stem and progenitor cells (HSPCs) early during infection and mobilize them transiently to the spleen to produce trained macrophages. Trained HSPCs are not only primed for myeloid cell production but also reprogramed to produce a greater amount of proinflammatory cytokines in response to a second challenge; additionally, their adoptive transfer is sufficient to protect mice against reinfection. Mechanistically, autocrine GM-CSF activation of HSPCs is responsible for the trained phenotype and essential for the vaccine-induced protection. Our findings reveal a fundamental role for HSPCs in the trained immune protective response, opening new avenues for disease prevention and treatment.

2021-12-06 | GSE184104 | GEO

Autocrine GM-CSF signaling programs hematopoietic stem and progenitor cells during Candida albicans infection for protection against reinfection

Project description:Autocrine GM-CSF signaling programs hematopoietic stem and progenitor cells during Candida albicans infection for protection against reinfection

| PRJNA763194 | ENA

Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes.

Project description:Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies.

| S-EPMC3864037 | biostudies-literature

Epithelial GM-CSF induction by Candida glabrata.

Project description:The main cytokine induced by the interaction of oral epithelial cells with C. glabrata is granulocyte monocyte colony-stimulating factor (GM-CSF); however, the mechanisms regulating this response are unknown. Based on previously published information on the interactions of C. albicans with oral epithelial cells, we hypothesized that interaction with viable C. glabrata triggers GM-CSF synthesis via NF-kappaB activation. We found that C. glabrata-induced GM-CSF synthesis was adhesion-dependent, enhanced by endocytosis, and required fungal viability. NF-kappaB activation was noted during interaction of epithelial cells with C. glabrata, and pre-treatment with an NF-kappaB inhibitor partly inhibited GM-CSF synthesis. Blocking TLR4 with anti-TLR4 antibody did not inhibit GM-CSF production. In contrast, an anti-CDw17 antibody triggered significant inhibition of NF-kappaB activation and GM-CSF synthesis. beta-glucans did not stimulate GM-CSF synthesis, suggesting that the CDw17/NF-kappaB/GM-CSF pathway may be beta-glucan-independent. This study provides new insights into the mechanism of GM-CSF induction by C. glabrata.

| S-EPMC2836204 | biostudies-literature

M-CSF improves protection against bacterial and fungal infections after hematopoietic stem/progenitor cell transplantation.

Project description:Myeloablative treatment preceding hematopoietic stem cell (HSC) and progenitor cell (HS/PC) transplantation results in severe myeloid cytopenia and susceptibility to infections in the lag period before hematopoietic recovery. We have previously shown that macrophage colony-stimulating factor (CSF-1; M-CSF) directly instructed myeloid commitment in HSCs. In this study, we tested whether this effect had therapeutic benefit in improving protection against pathogens after HS/PC transplantation. M-CSF treatment resulted in an increased production of mature myeloid donor cells and an increased survival of recipient mice infected with lethal doses of clinically relevant opportunistic pathogens, namely the bacteria Pseudomonas aeruginosa and the fungus Aspergillus fumigatus M-CSF treatment during engraftment or after infection efficiently protected from these pathogens as early as 3 days after transplantation and was effective as a single dose. It was more efficient than granulocyte CSF (G-CSF), a common treatment of severe neutropenia, which showed no protective effect under the tested conditions. M-CSF treatment showed no adverse effect on long-term lineage contribution or stem cell activity and, unlike G-CSF, did not impede recovery of HS/PCs, thrombocyte numbers, or glucose metabolism. These results encourage potential clinical applications of M-CSF to prevent severe infections after HS/PC transplantation.

| S-EPMC5068229 | biostudies-literature

Inhaled GM-CSF in neonatal mice provides durable protection against bacterial pneumonia.

Project description:Pneumonia poses profound health threats to preterm infants. Alveolar macrophages (AMs) eliminate inhaled pathogens while maintaining surfactant homeostasis. As AM development only occurs perinatally, therapies that accelerate AM maturation in preterms may improve outcomes. We tested therapeutic rescue of AM development in mice lacking the actin-bundling protein L-plastin (LPL), which exhibit impaired AM development and increased susceptibility to pneumococcal lung infection. Airway administration of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to LPL-/- neonates augmented AM production. Airway administration distinguishes the delivery route from prior human infant trials. Adult LPL-/- animals that received neonatal GM-CSF were protected from experimental pneumococcal challenge. No detrimental effects on surfactant metabolism or alveolarization were observed. Airway recombinant GM-CSF administration thus shows therapeutic promise to accelerate neonatal pulmonary immunity, protecting against bacterial pneumonia.

| S-EPMC6693910 | biostudies-literature

Loss of CD44 attenuates aberrant GM-CSF signaling in Kras G12D hematopoietic progenitor/precursor cells and prolongs the survival of diseased animals.

Project description: Not available

| S-EPMC3602969 | biostudies-literature

RUNX1-ETO (RE) murine hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF

Project description:GM-CSF signaling was previously reported to have a negative effect on a murine model of (8;21)-induced leukemia. Gene expression profiling of MigR1 (Mig) control and RUNX1-ETO (RE), the oncofusion protein generated from t(8;21), murine Lin-/c-Kit+ hematopoietic stem/progenitor cells (HSPCs) was conducted to further elucidate the mechanisms mediating the negative effect induced by GM-CSF signaling in t(8;21) cells,

2016-09-23 | GSE72567 | GEO

GM-CSF and IL-4 Fusion Cytokine Induces B Cell-Dependent Hematopoietic Regeneration.

Project description:Hematopoietic stem cells (HSCs) have the capacity to self-renew and differentiate into hematopoietic cells and have been utilized to replace diseased bone marrow for patients with cancers and blood disorders. Although remarkable progress has been made in developing new tools to manipulate HSCs for clinic use, there is still no effective method to expand HSCs in vivo for quick repopulation of hematopoietic cells following sublethal irradiation. We have recently described a novel synthetic cytokine that is derived from the fusion of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4; named as GIFT4), and we have now discovered that GIFT4 fusokine promotes long-term hematopoietic regeneration in a B cell-dependent manner. We found that GIFT4 treatment triggered a robust expansion of endogenous bone marrow HSCs and multipotent progenitors in vivo. Delivery of GIFT4 protein together with B cells rescued lethally irradiated mice. Moreover, adoptive transfer of autologous or allogeneic GIFT4-treated B cells (GIFT4-B cells) enhanced long-term hematopoietic recovery in radiated mice and prevented the mice from irradiation-induced death. Our data suggest that GIFT4 as well as GIFT4-B cells could serve as means to augment HSC engraftment in the setting of bone marrow transplantation for patients with hematological malignancy.

| S-EPMC5368424 | biostudies-literature

GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.

Project description:Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.

| S-EPMC7351110 | biostudies-literature

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