Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.

Abstract:

:Interferon Regulatory Factor 8 (IRF8) is required for development, maturation and expression of anti-microbial defenses of myeloid cells. BXH2 mice harbor a severely hypomorphic allele at Irf8 (Irf8(R294C)) that causes susceptibility to infection with intracellular pathogens including Mycobacterium tuberculosis. We report that BXH2 are completely resistant to the development of cerebral malaria (ECM) following Plasmodium berghei ANKA infection. Comparative transcriptional profiling of brain RNA as well as chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) was used to identify IRF8-regulated genes whose expression is associated with pathological acute neuroinflammation. Genes increased by infection were strongly enriched for IRF8 binding sites, suggesting that IRF8 acts as a transcriptional activator in inflammatory programs. These lists were enriched for myeloid-specific pathways, including interferon responses, antigen presentation and Th1 polarizing cytokines. We show that inactivation of several of these downstream target genes (including the Irf8 transcription partner Irf1) confers protection against ECM. ECM-resistance in Irf8 and Irf1 mutants is associated with impaired myeloid and lymphoid cells function, including production of IL12p40 and IFNγ. We note strong overlap between genes bound and regulated by IRF8 during ECM and genes regulated in the lungs of M. tuberculosis infected mice. This IRF8-dependent network contains several genes recently identified as risk factors in acute and chronic human inflammatory conditions. We report a common core of IRF8-bound genes forming a critical inflammatory host-response network.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Berghout J,Langlais D,Radovanovic I,Tam M,MacMicking JD,Stevenson MM,Gros P

doi

10.1371/journal.ppat.1003491

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

e1003491

issue

7

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-12-02976

journal_volume

9

pub_type

杂志文章
  • A gatekeeper chaperone complex directs translocator secretion during type three secretion.

    abstract::Many Gram-negative bacteria use Type Three Secretion Systems (T3SS) to deliver effector proteins into host cells. These protein delivery machines are composed of cytosolic components that recognize substrates and generate the force needed for translocation, the secretion conduit, formed by a needle complex and associa...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004498

    authors: Archuleta TL,Spiller BW

    更新日期:2014-11-06 00:00:00

  • Adhesion of Neisseria meningitidis to dermal vessels leads to local vascular damage and purpura in a humanized mouse model.

    abstract::Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggreg...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003139

    authors: Melican K,Michea Veloso P,Martin T,Bruneval P,Duménil G

    更新日期:2013-01-01 00:00:00

  • Dual expression profile of type VI secretion system immunity genes protects pandemic Vibrio cholerae.

    abstract::The Vibrio cholerae type VI secretion system (T6SS) assembles as a molecular syringe that injects toxic protein effectors into both eukaryotic and prokaryotic cells. We previously reported that the V. cholerae O37 serogroup strain V52 maintains a constitutively active T6SS to kill other Gram-negative bacteria while be...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003752

    authors: Miyata ST,Unterweger D,Rudko SP,Pukatzki S

    更新日期:2013-01-01 00:00:00

  • Venus kinase receptors control reproduction in the platyhelminth parasite Schistosoma mansoni.

    abstract::The Venus kinase receptor (VKR) is a single transmembrane molecule composed of an intracellular tyrosine kinase domain close to that of insulin receptor and an extracellular Venus Flytrap (VFT) structure similar to the ligand binding domain of many class C G protein coupled receptors. This receptor tyrosine kinase (RT...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004138

    authors: Vanderstraete M,Gouignard N,Cailliau K,Morel M,Hahnel S,Leutner S,Beckmann S,Grevelding CG,Dissous C

    更新日期:2014-05-29 00:00:00

  • NAD+-Glycohydrolase Promotes Intracellular Survival of Group A Streptococcus.

    abstract::A global increase in invasive infections due to group A Streptococcus (S. pyogenes or GAS) has been observed since the 1980s, associated with emergence of a clonal group of strains of the M1T1 serotype. Among other virulence attributes, the M1T1 clone secretes NAD+-glycohydrolase (NADase). When GAS binds to epithelial...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005468

    authors: Sharma O,O'Seaghdha M,Velarde JJ,Wessels MR

    更新日期:2016-03-03 00:00:00

  • Structure of a Spumaretrovirus Gag Central Domain Reveals an Ancient Retroviral Capsid.

    abstract::The Spumaretrovirinae, or foamy viruses (FVs) are complex retroviruses that infect many species of monkey and ape. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. However, there is a pau...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005981

    authors: Ball NJ,Nicastro G,Dutta M,Pollard DJ,Goldstone DC,Sanz-Ramos M,Ramos A,Müllers E,Stirnnagel K,Stanke N,Lindemann D,Stoye JP,Taylor WR,Rosenthal PB,Taylor IA

    更新日期:2016-11-09 00:00:00

  • EBV epitranscriptome reprogramming by METTL14 is critical for viral-associated tumorigenesis.

    abstract::Epstein-Barr virus (EBV) is a ubiquitous oncogenic virus that induces many cancers. N6-Methyladenosine (m6A) modification regulates many cellular processes. We explored the role of m6A in EBV gene regulation and associated cancers. We have comprehensively defined m6A modification of EBV latent and lytic transcripts. F...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007796

    authors: Lang F,Singh RK,Pei Y,Zhang S,Sun K,Robertson ES

    更新日期:2019-06-21 00:00:00

  • The secreted peptide PIP1 amplifies immunity through receptor-like kinase 7.

    abstract::In plants, innate immune responses are initiated by plasma membrane-located pattern recognition receptors (PRRs) upon recognition of elicitors, including exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Arabidopsis thaliana produces more than 1000 se...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1004331

    authors: Hou S,Wang X,Chen D,Yang X,Wang M,Turrà D,Di Pietro A,Zhang W

    更新日期:2014-09-04 00:00:00

  • The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria.

    abstract::The digestive tract is the first organ affected by the ingestion of foodborne bacteria. While commensal bacteria become resident, opportunistic or virulent bacteria are eliminated from the gut by the local innate immune system. Here we characterize a new mechanism of defense, independent of the immune system, in Droso...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007279

    authors: Benguettat O,Jneid R,Soltys J,Loudhaief R,Brun-Barale A,Osman D,Gallet A

    更新日期:2018-09-04 00:00:00

  • NsrR, GadE, and GadX interplay in repressing expression of the Escherichia coli O157:H7 LEE pathogenicity island in response to nitric oxide.

    abstract::Expression of genes of the locus of enterocyte effacement (LEE) is essential for adherence of enterohemorrhagic Escherichia coli (EHEC) to intestinal epithelial cells. Gut factors that may modulate LEE gene expression may therefore influence the outcome of the infection. Because nitric oxide (NO) is a critical effecto...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003874

    authors: Branchu P,Matrat S,Vareille M,Garrivier A,Durand A,Crépin S,Harel J,Jubelin G,Gobert AP

    更新日期:2014-01-01 00:00:00

  • The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion.

    abstract::Human Cytomegalovirus (HCMV) is a widespread pathogen, infection with which can cause severe disease for immunocompromised individuals. The complex changes wrought on the host's immune system during both productive and latent HCMV infection are well known. Infected cells are masked and manipulated and uninfected immun...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006454

    authors: Zischke J,Mamareli P,Pokoyski C,Gabaev I,Buyny S,Jacobs R,Falk CS,Lochner M,Sparwasser T,Schulz TF,Kay-Fedorov PC

    更新日期:2017-06-19 00:00:00

  • PKACs attenuate innate antiviral response by phosphorylating VISA and priming it for MARCH5-mediated degradation.

    abstract::Sensing of viral RNA by RIG-I-like receptors initiates innate antiviral response, which is mediated by the central adaptor VISA. How the RIG-I-VISA-mediated antiviral response is terminated at the late phase of infection is enigmatic. Here we identified the protein kinase A catalytic (PKAC) subunits α and β as negativ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006648

    authors: Yan BR,Zhou L,Hu MM,Li M,Lin H,Yang Y,Wang YY,Shu HB

    更新日期:2017-09-21 00:00:00

  • Antibody evasion by a gammaherpesvirus O-glycan shield.

    abstract::All gammaherpesviruses encode a major glycoprotein homologous to the Epstein-Barr virus gp350. These glycoproteins are often involved in cell binding, and some provide neutralization targets. However, the capacity of gammaherpesviruses for long-term transmission from immune hosts implies that in vivo neutralization is...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1002387

    authors: Machiels B,Lété C,Guillaume A,Mast J,Stevenson PG,Vanderplasschen A,Gillet L

    更新日期:2011-11-01 00:00:00

  • A major determinant of cyclophilin dependence and cyclosporine susceptibility of hepatitis C virus identified by a genetic approach.

    abstract::Since the advent of genome-wide small interfering RNA screening, large numbers of cellular cofactors important for viral infection have been discovered at a rapid pace, but the viral targets and the mechanism of action for many of these cofactors remain undefined. One such cofactor is cyclophilin A (CyPA), upon which ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1001118

    authors: Yang F,Robotham JM,Grise H,Frausto S,Madan V,Zayas M,Bartenschlager R,Robinson M,Greenstein AE,Nag A,Logan TM,Bienkiewicz E,Tang H

    更新日期:2010-09-23 00:00:00

  • HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses.

    abstract::Antiretroviral therapy, antibody and CD8+ T cell-mediated responses targeting human immunodeficiency virus-1 (HIV-1) exert selection pressure on the virus necessitating escape; however, the ability of CD4+ T cells to exert selective pressure remains unclear. Using a computational approach on HIV gag/pol/nef sequences ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005111

    authors: Erdmann N,Du VY,Carlson J,Schaefer M,Jureka A,Sterrett S,Yue L,Dilernia D,Lakhi S,Tang J,Sidney J,Gilmour J,Allen S,Hunter E,Heath S,Bansal A,Goepfert PA

    更新日期:2015-08-24 00:00:00

  • Trans-dominant inhibition of prion propagation in vitro is not mediated by an accessory cofactor.

    abstract::Previous studies identified prion protein (PrP) mutants which act as dominant negative inhibitors of prion formation through a mechanism hypothesized to require an unidentified species-specific cofactor termed protein X. To study the mechanism of dominant negative inhibition in vitro, we used recombinant PrP(C) molecu...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1000535

    authors: Geoghegan JC,Miller MB,Kwak AH,Harris BT,Supattapone S

    更新日期:2009-07-01 00:00:00

  • Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress.

    abstract::Ebola (EBOV) and Marburg (MARV) viruses are members of the Filoviridae family which cause outbreaks of hemorrhagic fever. The filovirus VP40 matrix protein is essential for virus assembly and budding, and its PPxY L-domain motif interacts with WW-domains of specific host proteins, such as Nedd4 and ITCH, to facilitate...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006132

    authors: Liang J,Sagum CA,Bedford MT,Sidhu SS,Sudol M,Han Z,Harty RN

    更新日期:2017-01-11 00:00:00

  • Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation.

    abstract::Viral infections impose major stress on the host cell. In response, stress pathways can rapidly deploy defence mechanisms by shutting off the protein synthesis machinery and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression,...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1008250

    authors: Brocard M,Iadevaia V,Klein P,Hall B,Lewis G,Lu J,Burke J,Willcocks MM,Parker R,Goodfellow IG,Ruggieri A,Locker N

    更新日期:2020-01-06 00:00:00

  • Group A Streptococcus secreted esterase hydrolyzes platelet-activating factor to impede neutrophil recruitment and facilitate innate immune evasion.

    abstract::The innate immune system is the first line of host defense against invading organisms. Thus, pathogens have developed virulence mechanisms to evade the innate immune system. Here, we report a novel means for inhibition of neutrophil recruitment by Group A Streptococcus (GAS). Deletion of the secreted esterase gene (de...

    journal_title:PLoS pathogens

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1371/journal.ppat.1002624

    authors: Liu M,Zhu H,Li J,Garcia CC,Feng W,Kirpotina LN,Hilmer J,Tavares LP,Layton AW,Quinn MT,Bothner B,Teixeira MM,Lei B

    更新日期:2012-01-01 00:00:00

  • SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing.

    abstract::Cyclic GMP-AMP (cGAMP) synthase (cGAS, a.k.a. MB21D1), a cytosolic DNA sensor, catalyzes formation of the second messenger 2'3'-cGAMP that activates the stimulator of interferon genes (STING) signaling. How the cGAS activity is modulated remains largely unknown. Here, we demonstrate that sentrin/SUMO-specific protease...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006156

    authors: Cui Y,Yu H,Zheng X,Peng R,Wang Q,Zhou Y,Wang R,Wang J,Qu B,Shen N,Guo Q,Liu X,Wang C

    更新日期:2017-01-17 00:00:00

  • Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection.

    abstract::Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006046

    authors: Fontana MF,de Melo GL,Anidi C,Hamburger R,Kim CY,Lee SY,Pham J,Kim CC

    更新日期:2016-12-06 00:00:00

  • Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication.

    abstract::Herpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate latent, chronic or productive states of infection. Human cytomegalovirus (CMV or HCMV), a ubiquitous β-herpesvirus, coordinates the expression of two viral genes, UL135 and UL138, which have opposing roles in ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005655

    authors: Buehler J,Zeltzer S,Reitsma J,Petrucelli A,Umashankar M,Rak M,Zagallo P,Schroeder J,Terhune S,Goodrum F

    更新日期:2016-05-24 00:00:00

  • Increased Programmed Death-Ligand 1 is an Early Epithelial Cell Response to Helicobacter pylori Infection.

    abstract::Helicobacter pylori (H. pylori) is the major risk factor for the development of gastric cancer. Our laboratory has reported that the Sonic Hedgehog (Shh) signaling pathway is an early response to infection that is fundamental to the initiation of H. pylori-induced gastritis. H. pylori also induces programmed death lig...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007468

    authors: Holokai L,Chakrabarti J,Broda T,Chang J,Hawkins JA,Sundaram N,Wroblewski LE,Peek RM Jr,Wang J,Helmrath M,Wells JM,Zavros Y

    更新日期:2019-01-31 00:00:00

  • Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool.

    abstract::Memory T cell inflation is a process in which a subset of cytomegalovirus (CMV) specific CD8 T cells continuously expands mainly during latent infection and establishes a large and stable population of effector memory cells in peripheral tissues. Here we set out to identify in vivo parameters that promote and limit CD...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1007785

    authors: Baumann NS,Welten SPM,Torti N,Pallmer K,Borsa M,Barnstorf I,Oduro JD,Cicin-Sain L,Oxenius A

    更新日期:2019-05-13 00:00:00

  • CdtR Regulates TcdA and TcdB Production in Clostridium difficile.

    abstract::Clostridium difficile is a global health burden and the leading cause of antibiotic-associated diarrhoea worldwide, causing severe gastrointestinal disease and death. Three well characterised toxins are encoded by this bacterium in two genetic loci, specifically, TcdB (toxin B) and TcdA (toxin A) in the Pathogenicity ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005758

    authors: Lyon SA,Hutton ML,Rood JI,Cheung JK,Lyras D

    更新日期:2016-07-14 00:00:00

  • Nematode neuropeptides as transgenic nematicides.

    abstract::Plant parasitic nematodes (PPNs) seriously threaten global food security. Conventionally an integrated approach to PPN management has relied heavily on carbamate, organophosphate and fumigant nematicides which are now being withdrawn over environmental health and safety concerns. This progressive withdrawal has left a...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1006237

    authors: Warnock ND,Wilson L,Patten C,Fleming CC,Maule AG,Dalzell JJ

    更新日期:2017-02-27 00:00:00

  • PML/TRIM19-Dependent Inhibition of Retroviral Reverse-Transcription by Daxx.

    abstract::PML (Promyelocytic Leukemia protein), also known as TRIM19, belongs to the family of tripartite motif (TRIM) proteins. PML is mainly expressed in the nucleus, where it forms dynamic structures known as PML nuclear bodies that recruit many other proteins, such as Sp100 and Daxx. While the role of PML/TRIM19 in antivira...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1005280

    authors: Dutrieux J,Maarifi G,Portilho DM,Arhel NJ,Chelbi-Alix MK,Nisole S

    更新日期:2015-11-13 00:00:00

  • Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae.

    abstract::Antigenic variation to evade host immunity has long been assumed to be a driving force of diversifying selection in pathogens. Colonization by Streptococcus pneumoniae, which is central to the organism's transmission and therefore evolution, is limited by two arms of the immune system: antibody- and T cell- mediated i...

    journal_title:PLoS pathogens

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1371/journal.ppat.1002989

    authors: Li Y,Gierahn T,Thompson CM,Trzciński K,Ford CB,Croucher N,Gouveia P,Flechtner JB,Malley R,Lipsitch M

    更新日期:2012-01-01 00:00:00

  • The plant actin cytoskeleton responds to signals from microbe-associated molecular patterns.

    abstract::Plants are constantly exposed to a large and diverse array of microbes; however, most plants are immune to the majority of potential invaders and susceptible to only a small subset of pathogens. The cytoskeleton comprises a dynamic intracellular framework that responds rapidly to biotic stresses and supports numerous ...

    journal_title:PLoS pathogens

    pub_type: 杂志文章

    doi:10.1371/journal.ppat.1003290

    authors: Henty-Ridilla JL,Shimono M,Li J,Chang JH,Day B,Staiger CJ

    更新日期:2013-01-01 00:00:00

  • Bacterial flagella: twist and stick, or dodge across the kingdoms.

    abstract::The flagellum organelle is an intricate multiprotein assembly best known for its rotational propulsion of bacteria. However, recent studies have expanded our knowledge of other functions in pathogenic contexts, particularly adherence and immune modulation, e.g., for Salmonella enterica, Campylobacter jejuni, Pseudomon...

    journal_title:PLoS pathogens

    pub_type: 杂志文章,评审

    doi:10.1371/journal.ppat.1004483

    authors: Rossez Y,Wolfson EB,Holmes A,Gally DL,Holden NJ

    更新日期:2015-01-15 00:00:00