Role of IL10 signaling in the circadian control of host response to Influenza infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE287759 | GEO | 2025/01/29
REPOSITORIES: GEO
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Project description:CD4+ Th1 cells producing IFN-g are required to eradicate intracellular pathogens, however if uncontrolled these cells can mediate immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells.
2023-08-24 | GSE197783 | GEO
Project description:Influenza A virus (IAV) infection causes an acute respiratory disease characterized by a strong inflammatory immune response and severe immunopathology. Pro-inflammatory mechanisms are well described in the murine IAV infection model, but less is known about the mechanisms leading to the resolution of inflammation. Here, we analyzed the contribution of monocytic myeloid-derived suppressor cells (mono-MDSC) to this process. An accumulation of mono-MDSC within the lungs was observed during the course of IAV infection and phenotypic characterization of these mono-MDSC by flow cytometry and RNA-Seq revealed an activated phenotype showing both pro- and anti-inflammatory features, including the expression of iNOS by a fraction of cells in an IFN-g-dependent manner. Mono-MDSC isolated from lungs of IAV-infected animals displayed suppressive activity when tested in vitro, and iNOS inhibitors could abrogate this suppressive activity. Collectively, our data suggest that during IAV infection monocytes can differentiate into mono-MDSC, which might contribute to the prevention of immunopathology during this life-threatening disease.
2015-10-01 | GSE62795 | GEO
Project description:CD4 T cells promote innate and adaptive immune responses, but how vaccine-elicited CD4 T cells contribute to immune protection remains unclear. Here we evaluated whether induction of virus-specific CD4 T cells by vaccination would protect mice against infection with chronic lymphocytic choriomeningitis virus (LCMV). Immunization with vaccines that selectively induced CD4 T cell responses resulted in catastrophic inflammation and mortality following challenge with a persistent form of LCMV. Immunopathology required antigen-specific CD4 T cells and was associated with a cytokine storm, generalized inflammation, and multi-organ system failure. Virus-specific CD8 T cells or antibodies abrogated the pathology. These data demonstrate that vaccine-elicited CD4 T cells in the absence of effective antiviral immune responses can trigger lethal immunopathology. Splenic GP66-specific CD4 T cells from mice immunized with either a LMwt vaccine (sham) or LMgp61 vaccine (CD4 vaccine) were purified by FACS on day 8 post-infection with LCMV clone 13
2014-12-04 | E-GEOD-63825 | biostudies-arrayexpress
Project description:After a century of the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its protection against homologous (Mycobacterium tuberculosis) or heterologous (e.g. influenza virus) infections is still limited. Here we show that systemic (intravenous) BCG vaccination (BCG-iv) provides significant protection against subsequent influenza A virus (IAV) infection in mice. We further demonstrate that the BCG-mediated cross-protection against IAV is largely due to the enrichment of conventional CD4+ αβ effector memory T cells that express high levels of CX3CR1hi in circulation trafficking into the lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent IFNγ production, which subsequently enhances long-term antimicrobial activity of the innate immune system like alveolar macrophages. Similarly, we uncover a prominent IFNγ signature in which its increased basal production was associated with enhanced BCG-mediated heterologous innate memory responses in BCG-vaccinated humans. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculous infections via a crosstalk between adaptive and innate memory responses.
2023-11-01 | GSE246201 | GEO
Project description:Maternal IL10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here we show that Il10 null mutant (Il10-/-) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4+ and CD8+ T cells compared with wild-type controls. Amongst these CD4+ cells, Foxp3+ Treg cells were substantially enriched, with 11-fold higher numbers at day 9.5 post coitum (pc). Lymph node hypertrophy in Il10-/- mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10-/- mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2 and Ifng. In vitro, Il10-/- Treg cells showed reduced steady state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4+Foxp3- T cells. We conclude that despite a substantially expanded Treg cell pool, diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10-/- mice. These findings suggest a pivotal role for IL10 in facilitating robust immune protection of the fetus from inflammatory challenge and suggest IL10 deficiency could contribute to human gestational disorders where altered T cell responses are implicated.
2015-07-30 | GSE71494 | GEO
Project description:CD4+ Th1 cells producing IFN-g are required to eradicate intracellular pathogens, however if uncontrolled these cells can mediate immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells. We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce Il10 gene expression in IL-12 plus IL-27 differentiated Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including Ifng, thus providing mechanisms for reinforcement of regulated Th1 cell responses.
2023-08-24 | GSE197782 | GEO
Project description:Disease tolerance is an evolutionarily conserved host defence strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against Influenza A virus (IAV) infection. Here we observe that β-glucan treatment reduced the morbidity and mortality against IAV infection, independent of host resistance (viral load). Increased survival of β-glucan treated mice against IAV is associated with the accumulation of neutrophils via RORgt+ T cells in the lung tissue. Using gain-and-loss-of-function approaches, we demonstrate that β-glucan reprogrammed neutrophils are essential for promoting disease tolerance, limiting pulmonary tissue damage, and enhancing survival against IAV infection. β-glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of neutrophils, which are less mature with higher mitochondrial mass utilizing mitochondrial oxidative (OXPHOS) metabolism. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells (HSCs) to generate neutrophils with a novel “regulatory” function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.
2024-11-22 | GSE248464 | GEO
Project description:Maternal IL10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here we show that Il10 null mutant (Il10-/-) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4+ and CD8+ T cells compared with wild-type controls. Amongst these CD4+ cells, Foxp3+ Treg cells were substantially enriched, with 11-fold higher numbers at day 9.5 post coitum (pc). Lymph node hypertrophy in Il10-/- mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10-/- mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2 and Ifng. In vitro, Il10-/- Treg cells showed reduced steady state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4+Foxp3- T cells. We conclude that despite a substantially expanded Treg cell pool, diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10-/- mice. These findings suggest a pivotal role for IL10 in facilitating robust immune protection of the fetus from inflammatory challenge and suggest IL10 deficiency could contribute to human gestational disorders where altered T cell responses are implicated. RNA was extracted from CD4+CD25+ lymphocytes isolated from para-aortic LNs of day 9.5 pc pregnant Il10+/+ or Il10-/- mice using miRNeasy Mini Kits (Qiagen Inc., Valencia, CA, USA) according to the manufacturer’s instructions. The concentration and purity of each RNA sample was determined using the Nanodrop Spectrophotometer (ND-1000, Nanodrop Technologies Inc., Wilmington, DE). RNA quality was determined using the RNA 6000 Pico Total RNA Kit (Agilent Technologies, Santa Clara CA) prior to use in microarray experiments. RNA with a RIN>7 was used in this study. For microarray analysis, RNA was pooled (from 2-4 mice per pool) resulting in four biological replicates of CD4+CD25+ cells from both Il10-/- and Il10+/+ mice. Microarray analysis was performed using Affymetrix Mouse Gene 2.0 ST Arrays at the Adelaide Microarray Centre. Total RNA was amplified using the Ovation PicoSL WTA System V2 (Nugen Inc., San Carlos, CA, USA) and MinElute Reaction Cleanup Kit (Qiagen Inc., Valencia, CA, USA), according to the manufacturer’s instructions, to provide 5 ?g of cRNA for each microarray. The microarray data was normalized and analyzed using Partek Genomics Suite (Partek Inc, MO). Raw data from the Affymetrix platform (.cel files) were imported and normalized using RMA background correction, Partek’s own GC content correction, and mean probe summarization.
2015-07-30 | E-GEOD-71494 | biostudies-arrayexpress
Project description:Miao2010 - Innate and adaptive immune
responses to primary Influenza A Virus infection
This model is described in the article:
Quantifying the early immune
response and adaptive immune response kinetics in mice infected
with influenza A virus.
Miao H, Hollenbaugh JA, Zand MS,
Holden-Wiltse J, Mosmann TR, Perelson AS, Wu H, Topham DJ.
J. Virol. 2010 Jul; 84(13):
6687-6698
Abstract:
Seasonal and pandemic influenza A virus (IAV) continues to
be a public health threat. However, we lack a detailed and
quantitative understanding of the immune response kinetics to
IAV infection and which biological parameters most strongly
influence infection outcomes. To address these issues, we use
modeling approaches combined with experimental data to
quantitatively investigate the innate and adaptive immune
responses to primary IAV infection. Mathematical models were
developed to describe the dynamic interactions between target
(epithelial) cells, influenza virus, cytotoxic T lymphocytes
(CTLs), and virus-specific IgG and IgM. IAV and immune kinetic
parameters were estimated by fitting models to a large data set
obtained from primary H3N2 IAV infection of 340 mice. Prior to
a detectable virus-specific immune response (before day 5), the
estimated half-life of infected epithelial cells is
approximately 1.2 days, and the half-life of free infectious
IAV is approximately 4 h. During the adaptive immune response
(after day 5), the average half-life of infected epithelial
cells is approximately 0.5 days, and the average half-life of
free infectious virus is approximately 1.8 min. During the
adaptive phase, model fitting confirms that CD8(+) CTLs are
crucial for limiting infected cells, while virus-specific IgM
regulates free IAV levels. This may imply that CD4 T cells and
class-switched IgG antibodies are more relevant for generating
IAV-specific memory and preventing future infection via a more
rapid secondary immune response. Also, simulation studies were
performed to understand the relative contributions of
biological parameters to IAV clearance. This study provides a
basis to better understand and predict influenza virus
immunity.
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2024-09-02 | BIOMD0000000546 | BioModels
Project description:In this study, we performed a genome-wide CRISPR screen in A549 cells to identify host genes that are required forInfluenza A virus (IAV) infection.Amongst the identified genes, WDR7, CCDC115, TMEM199 and CMTR1 conferred strong protection against IAV infection when they were CRISPR-deleted without impacting host cell fitness. To investigate the roles of these genes on the transciptomic states of the cell, we performed bulk RNA-sequencing of WDR7, CCDC115, TMEM199 and CMTR1 polyclonal knockout cells. We found that cells lacking WDR7, CCDC115 or TMEM199 up-regulates expression of lysosomal genes due to increased nuclear translocation of Transcription factor EB (TFEB), which hampers IAV entry. In addition,we report that CRISPR deletion of CMTR1 results in increased expression of Interferon-stimulated genes (ISGs) that also plays a role inblocking IAV infection.
2019-11-30 | GSE141171 | GEO