Spatial analysis of microglial and vascular responses following recurrent intranasal Group A Streptococcus infections
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PROVIDER: PRJNA912763 | ENA |
REPOSITORIES: ENA
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Project description:Peripheral infections can result in neurocognitive changes in many contexts, including after recurrent Group A Streptococcus (GAS) infections in children. To explore the underlying mechanisms, here we used an intranasal inoculation model to analyze nearly 200,000 cells from the mouse olfactory bulb (OB) by multiplexed error-robust fluorescent in situ hybridization (MERFISH). Upon repeated GAS inoculations, endothelial cells (ECs) responded by downregulating blood-brain barrier and extracellular matrix genes. Microglia upregulated response to interferon and antigen presentation genes and downregulated homeostatic microglia genes. We determined that microglia with higher expression of Streptococcus-responsive genes were localized to the outer glomerular layer of the OB, possibly due to their proximity to infiltrating CD4 T cells. Expression of homeostatic genes was correspondingly high in the inner granular layer of the OB.
2023-03-14 | GSE221106 | GEO
Project description:Peripheral infections can result in neuropsychiatric changes in many contexts, including after recurrent Group A Streptococcus (GAS) infections in children. To explore the underlying mechanisms, here we used an intranasal inoculation model to analyze more than 100,000 cells from the mouse olfactory bulb (OB) and nasal lymphoid tissue by single-cell RNA sequencing (scRNAseq). Upon repeated GAS inoculations, endothelial cells responded by downregulating blood-brain barrier (BBB)-specific genes, and microglia upregulated interferon-response, chemokine and antigen-presentation genes. To determine whether specific Th17 cytokines play distinct roles in producing this phenotype, we administered a neutralizing antibody against interleukin 17A (IL-17A), which decreased microglial expression of interferon-response and chemokine genes, but unexpectedly exacerbated levels of antigen presentation markers. Another Th17 cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) rescued a different subset of microglial transcripts.
2023-03-14 | GSE221724 | GEO
Project description:Effects of Th17 cytokines on microglial responses and the blood-brain barrier following recurrent intranasal Group A Streptococcus infections
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Project description:Peripheral infections can result in neuropsychiatric changes in many contexts, including after recurrent Group A Streptococcus (GAS) infections in children. In a mouse model of intranasal GAS inoculation, we have previously demonstrated in vivo that mice lacking Th17 cells, or the key Th17 cytokines interleukin 17A (IL-17A) or granulocyte-macrophage colony-stimulating factor (GM-CSF), have altered microglial responses. As an attempt to determine whether these cytokines have direct effects on microglia, we cultured primary microglia and incubated them with either interferon gamma (IFNg), IL-17A or GM-CSF for 24 hours, then collected RNA for bulk sequencing. Microglia treated with IFNg or GM-CSF displayed striking transcriptional shifts, including upregulation of many inflammatory genes. IL-17A treatment did not have a noticeable effect on the microglial transcriptome, likely due to the in vitro absence of IL-17A receptors, which are expressed by microglia in vivo.
2023-03-14 | GSE221715 | GEO
Project description:MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Herein, we observe that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provided protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogated the protection conferred by MV130 against Influenza A virus respiratory infection. MV130 induced reprogramming of mouse bone marrow progenitor cells and human monocytes, promoting an enhanced cytokine production that relied on metabolic and epigenetic shifts. Our results unveil that the mucosal a dministration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity. This SuperSeries is composed of the SubSeries listed below.
2021-11-10 | GSE183721 | GEO
Project description:Microglial cells are resident macrophages in the central nervous system (CNS) and play a pivotal role in the innate and adaptive immune responses against microbial infections. The immune functions of microglia are regulated by a milieu of cytokines including interferon (IFN)-gamma. We here performed a series of experiments to acertain the transcriptional profile of human fetal microglial cells at 1, 6, and 24 h after IFN-gamma treatment. Primary human microglial cells were either untreated or treated with 200u/ml IFN-gamma. Affymetrix U133A chips were utilized. Four different tissue samples (B18, O, W, and Y20) were analyzed at the three time points.
2007-08-03 | E-GEOD-1432 | biostudies-arrayexpress
Project description:Integrated transcriptome and metabolome analysis of mechanism on intranasal spray insulin against vascular dementia
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Project description:The 17q12 deletion syndrome (17q12DS) is a chromosomal aberration with a heterozygous deletion of a 1.4 megabases (Mb)‒spanning DNA sequence on the long arm of chromosome 17. The well-known clinical characteristics of 17q12DS include abnormalities of the kidney and urinary tracts, as well as neurodevelopmental disorders. However, in our cohort of 37 subjects with 17q12DS, we observed increased atopic disorders and recurrent sinopulmonary infections requiring prolonged courses of antibiotic therapies and/ or hospitalizations, raising the possible immune dysregulation in 17q12DS, a point that has not been previously addressed. We thus tested the hypothesis that individuals with 17q12DS[KI1] have altered T-cell function, contributing to recurrent infections and[KI2] atopy. Here we found that individuals with 17q12DS had a substantially decreased frequency of CD4+ T cells producing the T helper (Th) 1 cytokine IFN[KI3]-g but not Th2 and Th17 cytokines compared to age-matched healthy controls (HCs). RNA seq analysis of CD4+ T cells revealed decreased levels of TBX21 encoding the Th1 transcription factor T-bet, IFNG, and other Th1 chemokine encoding genes in subjects with 17q12DS compared to HCs. These findings were validated at the protein level using flow cytometry and multiplex assay. Our study is the first to demonstrated immune alterations in 17q12DS characterized by decreased T-bet and its downstream molecules such as IFN-γ. These findings warrant further investigations into the underlying mechanisms, which would inform precision therapy for individuals with 17q12DS.
2025-02-26 | GSE275915 | GEO
Project description:Aspergillus fumigatus is a saprophytic mold capable of reaching the human deep respiratory system causing different diseases. In this study we tried to detect the virulence mechanisms developed by the fungus, using four days evolution murine intranasal infection model. For that, we develop three independent infections, in order to obtain three independent fungus samples from the lung of the infected mice per day study. Finally, we had 12 independent samples from 12 different infected mice.
2018-12-03 | E-MTAB-5314 | biostudies-arrayexpress
Project description:Mucosal immunity plays a pivotal role in providing comprehensive protection against upper-airway infections and effectively limiting the shedding and transmission of SARS-CoV-2. Despite its critical importance, there remains a notable absence of nasal spray vaccines endorsed for global use by the World Health Organization. This could be due to the inability of current intranasal vaccines to induce strong mucosal and systemic responses in humans, thus urgently entailing a next-generation of intranasal COVID-19 vaccines with novel and safe technologies. In this study, we prepared a two-component intranasal vaccine that combines adenovirus vectors with a self-assembled subunit protein. Specifically, the adenovirus vector expresses the spike protein of XBB.1.5 variant (Ad5XBB.1.5), and were mixed with the recombinant protein that developed derived from the receptor binding domain (RBD) of XBB.1.5 (RBDXBB.1.5-HR). Combination of Ad5XBB.1.5 and RBDXBB.1.5-HR elicited superior humoral and cellular immunity against XBB.1.5-included variants compared with the individual components. Importantly, the STING signaling pathway was found to be crucial for the adjuvant effect of the adenovirus vector. In addition, to increase the broad-spectrum neutralizing capacities, a trimeric protein derived from the BA.5 variant (RBDBA.5-HR) was incorporated to formulate a three-component vaccine (Ad5XBB.1.5+RBDXBB.1.5-HR+RBDBA.5-HR), indicating the utilization of a combination of an adenovirus-vectored and subunit protein vaccines has the potential to serve as a next-generation intranasal vaccine platform. Of note, intranasally delivery of two-component vaccine provided protective immunity against live Omicron XBB.1.16 virus challenge in mice. Furthermore, the combination of adenovirus and subunit protein vaccine demonstrates excellent tolerability and safety in human subjects, and is able to induce enhanced mucosal immunity as well as high levels of sera neutralizing antibody in all participants. These findings underscore its suitability for clinical application in the prevention of SARS-CoV-2 variants encompassing XBB lineages.
2025-06-02 | GSE279004 | GEO