Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MARCH1 regulates anti-malarial immunity through interferon signaling and T cell activation

ABSTRACT: Malaria infection induces complex and diverse immune responses, including impairment of dendritic cell (DC) function and immune suppression that may contribute to the low vaccination antibody titers to some antigens in endemic populations. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early Plasmodium yoelii infection and identified a large number of interacting host and parasite genes/loci after trans-species expression quantitative trait loci (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene (march1) that was clustered with interferon stimulated genes. March1 can inhibit MAVS/STING induced IFN-I signaling and reverse inhibition of viral replication mediated by MAVS in vitro. However, in malaria-infected hosts, deficiency of march1 activates IFN signaling inhibitors such as SOCS1, SOCS3, and TRIM24, leading to reduced early (24h) serum IFN-I levels. Increased CD86+ DC populations and elevated levels of IFN-? and IL-10 produced by T cells day 4 post infection protect infected march1-/- mice. Malaria lysate stimulate MACRH1 expression, which reduces CD86+ DC cells and impairs T cell activation. This study reveals previous unknown functions of MARCH1 in innate response to malaria infections and provides potential avenues for activating anti-malaria immunity and enhancing vaccine efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE119944 | GEO | 2020/09/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Strain-specific Innate Immune Signaling Pathways Determine Malaria Parasitemia Dynamics and Host Mortality

Project description:Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within red blood cells (RBCs), thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi gene knockdown and knockout mice, we demonstrated that a strong IFN-I response triggered by RNA Polymerase III and melanoma differentiation-associated protein 5 (MDA5), not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine (PS) on infected RBC (iRBC) might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis. Spleen RNA from mice, 4 days post infection with Plasmodium yoelii (strain N67 or N67C), or mock infection (N). Replicates from 6 individual mice per condition.

2014-01-13 | E-GEOD-51329 | biostudies-arrayexpress

Strain-specific Innate Immune Signaling Pathways Determine Malaria Parasitemia Dynamics and Host Mortality

2014-01-13 | GSE51329 | GEO

Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12

Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.

2023-08-15 | GSE236763 | GEO

Systematic detection of host pathways universally inhibited by Plasmodium yoelii parasites for immune intervention

Project description:Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion and/or inhibition. To identify pathways commonly inhibited by malaria infection, we infected C67BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and linkages to parasite genetic loci. Strong interferon responses were observed after infection with N67 strain, whereas initial inhibition and later activation of hematopoiesis pathways were found after infection with 17XNL parasite. Inhibition of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. Treatment of infected mice with antibodies against T cell receptors OX40 or CD28 to activate malaria-inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.

2018-10-29 | GSE114718 | GEO

Cerebral malaria is regulated by host mediated changes in Plasmodium gene expression

Project description:Cerebral Malaria (CM), the deadliest complication of Plasmodium infection, is a complex and unpredictable disease. Currently, our understanding of the factors that trigger progression of malaria to CM is limited. Here, by infecting experimental CM (ECM) resistant (Balb/c) and ECM susceptible (C57BL/6) mice with ECM causing (ANKA) and non-ECM causing (NK65) Plasmodium berghei (Pb) parasite strains, we revealed that in resistant host, infection by ECM causing parasite develops similar to infection by non-ECM causing parasite in susceptible host in terms of parasite growth in host, disease course and host immune response against parasite. Our comparative gene expression analysis revealed that in Balb/c host, gene expression of Pb ANKA parasite is remarkably different from, the gene expression of Pb ANKA in C57BL/6 but similar to the gene expression of non-ECM causing Pb NK65 in C57BL/6. Thus, host has a critical influence on parasite behavior which ultimately determines the course of malaria disease.

2023-02-21 | GSE215359 | GEO

Distinct transcriptomic signatures define febrile malaria depending on initial infective states, asymptomatic or uninfected

Project description:Cumulative malaria parasite exposure in endemic regions often results in the acquisition of partial immunity and asymptomatic infections. There is limited information on how host-parasite interactions mediate maintenance of chronic symptomless infections that sustain malaria transmission. Here, we have determined the gene expression profiles of the parasite population and the corresponding host peripheral blood mononuclear cells (PBMCs) from 21 children (<15 years). We compared children who were defined as uninfected, asymptomatic and those with febrile malaria. Children with asymptomatic infections had a parasite transcriptional profile characterized by a bias toward trophozoite stage (~12 hours-post invasion) parasites and low parasite levels, while earlier ring stage parasites were characteristic of febrile malaria. The host response of asymptomatic children was characterized by downregulated transcription of genes associated with inflammatory responses, compared with children with febrile malaria, which may lead to less cytoadherence of more mature parasite stages. Interestingly, the host responses during febrile infections that followed an asymptomatic infection featured stronger inflammatory responses, whereas the febrile host responses from previously uninfected children featured increased humoral immune responses. The priming effect of prior asymptomatic infection may explain the blunted acquisition of antibody responses seen to malaria antigens following natural exposure or vaccination in malaria endemic areas.

2024-02-14 | GSE240643 | GEO

Expression data from HCV infected hepatoma carcinoma cell line Huh7-MAVSR cells

Project description:Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. HCV-encoded NS3/4 serine protease can subvert host innate immune responses by cleaving MAVS, a critical adaptor protein in the RLR-mediated IFN signaling. To study innate immunity in the context of HCV infection, we constructed Huh7-MAVSR cells which express a mutant MAVS resistant to NS3/4A cleavage. HCV infection induces robust IFN response in Huh7-MAVSR cells, providing a cellular system to study antiviral innate immune response against HCV infection. To analyze host innate antiviral effectors against HCV infection, we performed an mRNA microarray analysis in the HCV-infected Huh7-MAVSR cells.

2018-02-08 | GSE110312 | GEO

Transcriptomic analysis of Plasmodium PBANKA, PBSLTRiP-KO, PB268-KO parasite infected and uninfected host cell

Project description:Liver stage of malaria parasite exports SLTRiP and PB268 to the cytosol of parasite infected host cell. To know the host genes perturbed by WT-PBANKA, SLTRiP-KO and PB268-KO parasite growth, we did transcriptomic sequencing of infected host cells. We did mRNA sequencing of four samples for comparative analysis of WT and PB-knockout parasites infected host cells at 22 hours of post sporozoites infection.

2016-01-01 | GSE53292 | GEO

MARCH1 controls an exhaustion-like program of effector CD4+ T cells promoting allergic airway inflammation

Project description:Persistent antigenic signalling leads to T cell exhaustion, a dysfunctional state arising in many chronic infections and cancers. Little is known concerning mechanisms limiting exhaustion in immune stimulatory diseases such as asthma. We report that membrane-associated RING-CH1 (MARCH1), the ubiquitin ligase that mediates surface turnover of MHCII and CD86 in professional APCs, plays an essential role in restraining exhaustion of effector CD4+ T cells in a mouse model of asthma. Mice lacking MARCH1 or the ubiquitin acceptor sites of MHCII and CD86 exhibited increased MHCII and CD86 surface expression on lung APCs, and this increase promoted enhanced expression of immune inhibitory receptors by effector CD4+ T cells and inhibited their proliferation. Remarkably, ablation of MARCH1 in mice with established asthma reduced airway infiltration of eosinophils and Th2 cells. Thus, MARCH1 controls exhaustion of effector CD4+ T cells during allergic airway inflammation and may serve as a therapeutic target for asthma.

2022-08-24 | GSE211511 | GEO

Genome-wide interactions of mouse-Plasmodium yoelii parasite and identification of regulators of type I interferon response

Project description:An invading pathogen will trigger specific host responses, which can be explored to identify genes functioning in pathogen recognition and elimination. Here we performed trans-species expression quantitative trait locus (ts-eQTL) analysis using genotypes of the Plasmodium yoelii malaria parasite and phenotypes of mouse gene expression. We significantly (LOD score≥3.0) linked 1,054 host genes to many parasite genetic loci. Clustering genome-wide pattern of LOD scores (GPLSs), which produced results different from those of direct expression level clustering, grouped host genes functioning in related pathways together, allowing accurate functional prediction of unknown genes. As proof of principle, 14 of 15 randomly selected genes unknown, but predicted to function in type I interferon (IFN-I) responses, were experimentally verified using gene over expression, shRNA knockdown, viral infection, and/or infection of KO mice. This study demonstrates an effective strategy for studying gene function, establishes a functional gene database, and identifies regulators in IFN-I pathways.

2015-06-01 | GSE63611 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data