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Article: Smads keep TABs on inflammation.

Seth, Rashu B / Chen, Zhijian J

2007 Volume 8, Issue 5, Page(s) 477–478

MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Humans ; Inflammation/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Signal Transduction/physiology ; Smad7 Protein/metabolism ; Smad7 Protein/physiology ; Trans-Activators/genetics ; Trans-Activators/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Intracellular Signaling Peptides and Proteins ; Smad7 Protein ; TAB2 protein, human ; TAB3 protein, human ; Trans-Activators
Language	English
Publishing date	2007-05
Publishing country	United States
Document type	Comment ; News
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/ni0507-477
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Zs.MG 42: Show issues

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Article ; Online: Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation.

Senigl, Filip / Maman, Yaakov / Dinesh, Ravi K / Alinikula, Jukka / Seth, Rashu B / Pecnova, Lubomira / Omer, Arina D / Rao, Suhas S P / Weisz, David / Buerstedde, Jean-Marie / Aiden, Erez Lieberman / Casellas, Rafael / Hejnar, Jiri / Schatz, David G

Cell reports

2019 Volume 29, Issue 12, Page(s) 3902–3915.e8

Abstract: ... B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers ...

Abstract	Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible ("hot") and resistant ("cold") to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs.
MeSH term(s)	Cell Line, Tumor ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; Enhancer Elements, Genetic/genetics ; HEK293 Cells ; Humans ; Lentivirus ; Male ; Mutation/genetics ; Plasmids/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Somatic Hypermutation, Immunoglobulin/genetics
Chemical Substances	RNA Polymerase II (EC 2.7.7.-) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2019-12-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.11.039
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Article ; Online: Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Filip Senigl / Yaakov Maman / Ravi K. Dinesh / Jukka Alinikula / Rashu B. Seth / Lubomira Pecnova / Arina D. Omer / Suhas S.P. Rao / David Weisz / Jean-Marie Buerstedde / Erez Lieberman Aiden / Rafael Casellas / Jiri Hejnar / David G. Schatz

Cell Reports, Vol 29, Iss 12, Pp 3902-3915.e

2019 Volume 8

Abstract: ... polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs ...

Abstract	Summary: Somatic hypermutation (SHM) introduces point mutations into immunoglobulin (Ig) genes but also causes mutations in other parts of the genome. We have used lentiviral SHM reporter vectors to identify regions of the genome that are susceptible (“hot”) and resistant (“cold”) to SHM, revealing that SHM susceptibility and resistance are often properties of entire topologically associated domains (TADs). Comparison of hot and cold TADs reveals that while levels of transcription are equivalent, hot TADs are enriched for the cohesin loader NIPBL, super-enhancers, markers of paused/stalled RNA polymerase 2, and multiple important B cell transcription factors. We demonstrate that at least some hot TADs contain enhancers that possess SHM targeting activity and that insertion of a strong Ig SHM-targeting element into a cold TAD renders it hot. Our findings lead to a model for SHM susceptibility involving the cooperative action of cis-acting SHM targeting elements and the dynamic and architectural properties of TADs. : Senigl et al. show that genome susceptibility to somatic hypermutation (SHM) is confined within topologically associated domains (TADs) and is linked to markers of strong enhancers and stalled transcription and high levels of the cohesin loader NIPBL. Insertion of an ectopic SHM targeting element renders an entire TAD susceptible to SHM. Keywords: somatic hypermutation, activation induced deaminase, topologically associated domain, chromatin structure, chromatin loop extrusion, transcription factor
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article: Antiviral innate immunity pathways.

Seth, Rashu B / Sun, Lijun / Chen, Zhijian J

Cell research

2006 Volume 16, Issue 2, Page(s) 141–147

Abstract: Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. ...

Abstract	Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. The TLR pathway induces interferon production through several signaling proteins that ultimately lead to the activation of the transcription factors NF-kappaB, IRF3 and IRF7. The other antiviral pathway uses the RNA helicase RIG-I as the receptor for intracellular viral double-stranded RNA. RIG-I activates NF-kappaB and IRFs through the recently identified adaptor protein MAVS, a CARD domain containing protein that resides in the mitochondrial membrane. MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus (HCV), which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; DEAD Box Protein 58 ; DEAD-box RNA Helicases/metabolism ; Immunity, Innate/physiology ; Interferon Type I/genetics ; Interferon Type I/metabolism ; Models, Biological ; Signal Transduction/physiology ; Toll-Like Receptors/metabolism ; Viruses/genetics ; Viruses/immunology ; Viruses/pathogenicity
Chemical Substances	Adaptor Proteins, Signal Transducing ; Interferon Type I ; Toll-Like Receptors ; VISA protein, mouse ; Ddx58 protein, mouse (EC 3.6.1.-) ; DEAD Box Protein 58 (EC 3.6.4.13) ; DEAD-box RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2006-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/sj.cr.7310019
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Zs.A 5283: Show issues

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Article: Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.

Seth, Rashu B / Sun, Lijun / Ea, Chee-Kwee / Chen, Zhijian J

Cell

2005 Volume 122, Issue 5, Page(s) 669–682

Abstract: Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta). Herein, we report the ... ...

Abstract	Viral infection triggers host innate immune responses through activation of the transcription factors NF-kappaB and IRF 3, which coordinately regulate the expression of type-I interferons such as interferon-beta (IFN-beta). Herein, we report the identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection. Silencing of MAVS expression through RNA interference abolishes the activation of NF-kappaB and IRF 3 by viruses, thereby permitting viral replication. Conversely, overexpression of MAVS induces the expression of IFN-beta through activation of NF-kappaB and IRF 3, thus boosting antiviral immunity. Epistasis experiments show that MAVS is required for the phosphorylation of IRF 3 and IkappaB and functions downstream of RIG-I, an intracellular receptor for viral RNA. MAVS contains an N-terminal CARD-like domain and a C-terminal transmembrane domain, both of which are essential for MAVS signaling. The transmembrane domain targets MAVS to the mitochondria, implicating a new role of mitochondria in innate immunity.
MeSH term(s)	Amino Acid Sequence ; Animals ; Cell Line ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Bacterial/genetics ; Gene Silencing ; HeLa Cells ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3 ; Interferon Regulatory Factor-7 ; Interferon-beta/immunology ; Interferons/immunology ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Membrane Proteins/physiology ; Mitochondria/immunology ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/immunology ; Mitochondrial Proteins/physiology ; Molecular Sequence Data ; NF-kappa B/metabolism ; Protein-Serine-Threonine Kinases/immunology ; RNA, Double-Stranded/immunology ; Respirovirus Infections/immunology ; Respirovirus Infections/virology ; Sendai virus/genetics ; Sendai virus/immunology ; Sequence Alignment ; Signal Transduction/immunology ; Transcription Factors/metabolism ; Virus Replication/immunology
Chemical Substances	DNA-Binding Proteins ; IRF3 protein, human ; IRF7 protein, human ; Interferon Regulatory Factor-3 ; Interferon Regulatory Factor-7 ; Membrane Proteins ; Mitochondrial Proteins ; NF-kappa B ; RNA, Double-Stranded ; Transcription Factors ; Interferon-beta (77238-31-4) ; Interferons (9008-11-1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2005-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2005.08.012
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article: Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.

Li, Xiao-Dong / Sun, Lijun / Seth, Rashu B / Pineda, Gabriel / Chen, Zhijian J

Proceedings of the National Academy of Sciences of the United States of America

2005 Volume 102, Issue 49, Page(s) 17717–17722

Abstract: Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. ...

Abstract	Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the mitochondrial antiviral signaling protein, MAVS, that activates NF-kappaB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host-pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
MeSH term(s)	Amino Acid Sequence ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cell Line ; Cysteine/genetics ; Cysteine/metabolism ; Hepacivirus/enzymology ; Hepacivirus/immunology ; Hepacivirus/physiology ; Humans ; Immunity, Innate/drug effects ; Immunity, Innate/immunology ; Interferon-beta/pharmacology ; Intracellular Signaling Peptides and Proteins ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Molecular Sequence Data ; Protein Binding ; Sequence Alignment ; Signal Transduction/drug effects ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/metabolism ; Virus Replication
Chemical Substances	Carrier Proteins ; Intracellular Signaling Peptides and Proteins ; Mitochondrial Proteins ; NS3 protein, hepatitis C virus ; NS4A cofactor peptide, Hepatitis C virus ; Viral Nonstructural Proteins ; Viral Proteins ; Interferon-beta (77238-31-4) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2005-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0508531102
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Article: The specific and essential role of MAVS in antiviral innate immune responses.

Sun, Qinmiao / Sun, Lijun / Liu, Hong-Hsing / Chen, Xiang / Seth, Rashu B / Forman, James / Chen, Zhijian J

Immunity

2006 Volume 24, Issue 5, Page(s) 633–642

Abstract: The mitochondrial antiviral signaling protein (MAVS) mediates the activation of NFkappaB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by ... ...

Abstract	The mitochondrial antiviral signaling protein (MAVS) mediates the activation of NFkappaB and IRFs and the induction of interferons in response to viral infection. In vitro studies have also suggested that MAVS is required for interferon induction by cytosolic DNA, but the in vivo evidence is lacking. By generating MAVS-deficient mice, here we show that loss of MAVS abolished viral induction of interferons and prevented the activation of NFkappaB and IRF3 in multiple cell types, except plasmacytoid dendritic cells (pDCs). However, MAVS was not required for interferon induction by cytosolic DNA or by Listeria monocytogenes. Mice lacking MAVS were viable and fertile, but they failed to induce interferons in response to poly(I:C) stimulation and were severely compromised in immune defense against viral infection. These results provide the in vivo evidence that the cytosolic viral signaling pathway through MAVS is specifically required for innate immune responses against viral infection.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/immunology ; Animals ; Blotting, Southern ; Blotting, Western ; Fibroblasts/immunology ; Fibroblasts/metabolism ; Fibroblasts/microbiology ; Immunity, Innate ; Interferon Regulatory Factor-3/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferons/immunology ; Interferons/metabolism ; Listeriosis/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Mice, Mutant Strains ; Mitochondrial Proteins/deficiency ; Mitochondrial Proteins/immunology ; NF-kappa B/immunology ; NF-kappa B/metabolism ; Rhabdoviridae Infections/immunology ; Vesicular stomatitis Indiana virus/immunology ; Virus Diseases/immunology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Interferon Regulatory Factor-3 ; Irf3 protein, mouse ; Mitochondrial Proteins ; NF-kappa B ; Interferons (9008-11-1)
Language	English
Publishing date	2006-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2006.04.004
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 69: Show issues

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Article: TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.

Kanayama, Atsuhiro / Seth, Rashu B / Sun, Lijun / Ea, Chee-Kwee / Hong, Mei / Shaito, Abdullah / Chiu, Yu-Hsin / Deng, Li / Chen, Zhijian J

Molecular cell

2004 Volume 15, Issue 4, Page(s) 535–548

Abstract: The activation of NF-kappaB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63- ... ...

Abstract	The activation of NF-kappaB and IKK requires an upstream kinase complex consisting of TAK1 and adaptor proteins such as TAB1, TAB2, or TAB3. TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains. Here we present evidence that TAB2 and TAB3 are receptors that bind preferentially to lysine 63-linked polyubiquitin chains through a highly conserved zinc finger (ZnF) domain. Mutations of the ZnF domain abolish the ability of TAB2 and TAB3 to bind polyubiquitin chains, as well as their ability to activate TAK1 and IKK. Significantly, replacement of the ZnF domain with a heterologous ubiquitin binding domain restored the ability of TAB2 and TAB3 to activate TAK1 and IKK. We also show that TAB2 binds to polyubiquitinated RIP following TNFalpha stimulation. These results indicate that polyubiquitin binding domains represent a new class of signaling domains that regulate protein kinase activity through a nonproteolytic mechanism.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Amino Acid Sequence ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Enzyme Activation ; Humans ; I-kappa B Kinase ; Interleukin-1/metabolism ; Intracellular Signaling Peptides and Proteins ; MAP Kinase Kinase Kinases/metabolism ; Models, Biological ; Molecular Sequence Data ; NF-kappa B/metabolism ; Polyubiquitin/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism ; Proteins/genetics ; Proteins/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases ; Sequence Alignment ; Signal Transduction/physiology ; TNF Receptor-Associated Factor 6 ; Tumor Necrosis Factor-alpha/metabolism ; Zinc Fingers
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Interleukin-1 ; Intracellular Signaling Peptides and Proteins ; NF-kappa B ; Proteins ; TAB2 protein, human ; TAB3 protein, human ; TNF Receptor-Associated Factor 6 ; Tumor Necrosis Factor-alpha ; Polyubiquitin (120904-94-1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; RIPK1 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; CHUK protein, human (EC 2.7.11.10) ; I-kappa B Kinase (EC 2.7.11.10) ; IKBKB protein, human (EC 2.7.11.10) ; IKBKE protein, human (EC 2.7.11.10) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25)
Language	English
Publishing date	2004-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2004.08.008
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Article ; Online: RAG1 targeting in the genome is dominated by chromatin interactions mediated by the non-core regions of RAG1 and RAG2.

Maman, Yaakov / Teng, Grace / Seth, Rashu / Kleinstein, Steven H / Schatz, David G

Nucleic acids research

2016 Volume 44, Issue 20, Page(s) 9624–9637

Abstract: ... predicted by our model correlate well with observed patterns of RAG1-mediated breaks in human pro-B ...

Abstract	The RAG1/RAG2 endonuclease initiates V(D)J recombination at antigen receptor loci but also binds to thousands of places outside of these loci. RAG2 localizes directly to lysine 4 trimethylated histone 3 (H3K4me3) through a plant homeodomain (PHD) finger. The relative contribution of RAG2-dependent and RAG1-intrinsic mechanisms in determining RAG1 binding patterns is not known. Through analysis of deep RAG1 ChIP-seq data, we provide a quantitative description of the forces underlying genome-wide targeting of RAG1. Surprisingly, sequence-specific DNA binding contributes minimally to RAG1 targeting outside of antigen receptor loci. Instead, RAG1 binding is driven by two distinct modes of interaction with chromatin: the first is driven by H3K4me3, promoter-focused and dependent on the RAG2 PHD, and the second is defined by H3K27Ac, enhancer-focused and dependent on 'non-core' portions of RAG1. Based on this and additional chromatin and genomic features, we formulated a predictive model of RAG1 targeting to the genome. RAG1 binding sites predicted by our model correlate well with observed patterns of RAG1-mediated breaks in human pro-B acute lymphoblastic leukemia. Overall, this study provides an integrative model for RAG1 genome-wide binding and off-target activity and reveals a novel role for the RAG1 non-core region in RAG1 targeting.
MeSH term(s)	Animals ; Binding Sites ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin Immunoprecipitation ; Genome ; Genomic Instability ; High-Throughput Nucleotide Sequencing ; Histones/metabolism ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Nucleotide Motifs ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Domains and Motifs ; Recombination, Genetic ; V(D)J Recombination
Chemical Substances	Chromatin ; Histones ; Homeodomain Proteins
Language	English
Publishing date	2016-11-16
Publishing country	England
Document type	Journal Article
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkw633
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Article ; Online: Bacterial genome-wide association study substantiates papGII of Escherichia coli as a major risk factor for urosepsis.

Cuénod, Aline / Agnetti, Jessica / Seth-Smith, Helena M B / Roloff, Tim / Wälchli, Denise / Shcherbakov, Dimitri / Akbergenov, Rashid / Tschudin-Sutter, Sarah / Bassetti, Stefano / Siegemund, Martin / Nickel, Christian H / Moran-Gilad, Jacob / Keys, Timothy G / Pflüger, Valentin / Thomson, Nicholas R / Egli, Adrian

Genome medicine

2023 Volume 15, Issue 1, Page(s) 89

Abstract: Background: Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, often caused by uropathogenic Escherichia coli. Multiple bacterial virulence factors or patient characteristics have been linked separately to ... ...

Abstract	Background: Urinary tract infections (UTIs) are among the most common bacterial infections worldwide, often caused by uropathogenic Escherichia coli. Multiple bacterial virulence factors or patient characteristics have been linked separately to progressive, more invasive infections. In this study, we aim to identify pathogen- and patient-specific factors that drive the progression to urosepsis by jointly analysing bacterial and host characteristics. Methods: We analysed 1076 E. coli strains isolated from 825 clinical cases with UTI and/or bacteraemia by whole-genome sequencing (Illumina). Sequence types (STs) were determined via srst2 and capsule loci via fastKaptive. We compared the isolates from urine and blood to confirm clonality. Furthermore, we performed a bacterial genome-wide association study (bGWAS) (pyseer) using bacteraemia as the primary clinical outcome. Clinical data were collected by an electronic patient chart review. We concurrently analysed the association of the most significant bGWAS hit and important patient characteristics with the clinical endpoint bacteraemia using a generalised linear model (GLM). Finally, we designed qPCR primers and probes to detect papGII-positive E. coli strains and prospectively screened E. coli from urine samples (n = 1657) at two healthcare centres. Results: Our patient cohort had a median age of 75.3 years (range: 18.00-103.1) and was predominantly female (574/825, 69.6%). The bacterial phylogroups B2 (60.6%; 500/825) and D (16.6%; 137/825), which are associated with extraintestinal infections, represent the majority of the strains in our collection, many of which encode a polysaccharide capsule (63.4%; 525/825). The most frequently observed STs were ST131 (12.7%; 105/825), ST69 (11.0%; 91/825), and ST73 (10.2%; 84/825). Of interest, in 12.3% (13/106) of cases, the E. coli pairs in urine and blood were only distantly related. In line with previous bGWAS studies, we identified the gene papGII (p-value < 0.001), which encodes the adhesin subunit of the E. coli P-pilus, to be associated with 'bacteraemia' in our bGWAS. In our GLM, correcting for patient characteristics, papGII remained highly significant (odds ratio = 5.27, 95% confidence interval = [3.48, 7.97], p-value < 0.001). An independent cohort of cases which we screened for papGII-carrying E. coli at two healthcare centres further confirmed the increased relative frequency of papGII-positive strains causing invasive infection, compared to papGII-negative strains (p-value = 0.033, chi-squared test). Conclusions: This study builds on previous work linking papGII with invasive infection by showing that it is a major risk factor for progression from UTI to bacteraemia that has diagnostic potential.
MeSH term(s)	Humans ; Female ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Male ; Genome-Wide Association Study ; Escherichia coli Infections/diagnosis ; Urinary Tract Infections/diagnosis ; Urinary Tract Infections/microbiology ; Risk Factors ; Virulence Factors/genetics ; Sepsis ; Bacteremia ; Uropathogenic Escherichia coli/genetics ; Anti-Bacterial Agents
Chemical Substances	Virulence Factors ; Anti-Bacterial Agents
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-023-01243-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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