Innate cells and STAT1-dependent signals orchestrate vaccine-induced protection against invasive Cryptococcus infection
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ABSTRACT:
PROVIDER: PRJNA1131807 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29706801_1.fastq.gz | Fastqsanger.gz | |||
| SRR29706801_2.fastq.gz | Fastqsanger.gz | |||
| SRR29706802_1.fastq.gz | Fastqsanger.gz | |||
| SRR29706802_2.fastq.gz | Fastqsanger.gz | |||
| SRR29706803_1.fastq.gz | Fastqsanger.gz |
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Project description:Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2+ monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2+ cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c+ cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection.
2024-09-17 | GSE271485 | GEO
Project description:Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies, we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2+ monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2+ cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c+ cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection.IMPORTANCEThe number of patients susceptible to invasive fungal infections across the world continues to rise at an alarming pace yet current antifungal drugs are often inadequate. Immune-based interventions and novel antifungal vaccines hold the promise of significantly improving patient outcomes. In previous studies, we identified a Cryptococcus neoformans mutant strain (Fbp1-deficient) as a potent, heat-inactivated vaccine candidate capable of inducing homologous and heterologous antifungal protection. In this study, we used a combination of methods together with a cohort of conditional knockout mouse strains to interrogate the roles of innate cells in the orchestration of vaccine-induced antifungal protection. We uncovered novel roles for neutrophils and monocytes as coordinators of a STAT1-dependent cascade of responses that mediate vaccine-induced protection against invasive cryptococcosis. This new knowledge will help guide the future development of much-needed antifungal vaccines.
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Project description:Klebsiella pneumoniae (KP) are extracellular Gram-negative bacteria that cause infections in lower respiratory and urinary tract, and bloodstream. STAT1 is a master transcription factor that acts to maintain T-cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T-cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found STAT1-deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil-recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, as myeloid cell-specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed similar bacterial burden in lung, liver, and kidney as WT littermates. Surprisingly, IL-17 producing CD4+ T-cells infiltrated Stat1-/- mice lungs early during KP infection. Increase in Th17-cells in the lung was not due to preexisting immunity against KP and were consistent with circulating rather than tissue-resident CD4+ T-cells. However, blocking global IL17 signaling with anti-IL17-RC administration led to increased proliferation and dissemination of KP, suggesting IL17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T-cells reduced Stat1-/- mice lung bacterial burden indicating early CD4+ T-cell activation in the setting of global STAT1-deficiency is pathogenic. Altogether, our findings suggest STAT1 employs myeloid cell-extrinsic mechanisms to regulate neutrophil responses and provide protection against invasive KP by restricting non-specific CD4+ T-cell activation and immunopathology in the lung.
2024-01-10 | GSE251767 | GEO
Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).
2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress
Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape.
2013-12-31 | GSE43334 | GEO
Project description:STAT1 employs myeloid cell-extrinsic mechanisms to regulate the neutrophil response and provide protection against invasive Klebsiella pneumoniae lung infection
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Project description:Pancreatic Gene Expression from Wild-Type, Stat1-Transgenic, and Stat1-CC-Transgenic Mice. This data was part of the set of data utilized to identify PARP9/DTX3L as a novel antiviral gene. Keywords: transgene state analysis RNA was extracted from the pancreas of 3 mice per genotype (wild-type, Stat1-Transgenic, Stat1-CC-Transgenic). Comparisons were made between Stat1-Transgenic and Stat1-CC-Transgenic mice.
2015-09-01 | E-GEOD-61414 | biostudies-arrayexpress
Project description:The transcription factor Signal Transducer and Activator of Transcription (STAT) 1 is activated by Interferon gamma (IFNγ) but also Lipopolysaccharide (LPS) is the trigger of inflammation. STAT1 together with downstream activated Interferon Regulatory Factors (IRF) create a platform for signal integration between IFNγ and the Toll-Like Receptor (TLR) 4 ligand in immune cells. Little is known about the role of STAT1 and IRFs on potential synergism between LPS- and INFγ-signaling in cells from the vasculature. We investigated whether vascular cells can promote inflammatory signaling by the STAT1-IRFs pathway.
2014-11-04 | GSE49519 | GEO
Project description:STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing Stat1-Y701F. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo suggesting a so-far unknown cytoplasmic function. Using immunofluorescence technology we uncovered the recruitment of STAT1 to the immunological synapse during NK cell killing. A Stat1ind mouse expressing FLAG-tagged STAT1α was used to study the STAT1α interactome in NK cells. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. We propose a novel function for STAT1 in the immunological synapse of NK cells regulating tumor surveillance and cytotoxicity.
2016-10-07 | PXD002206 | Pride
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