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  • 1
    Publication Date: 2008-08-12
    Description: West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136529/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krishnan, Manoj N -- Ng, Aylwin -- Sukumaran, Bindu -- Gilfoy, Felicia D -- Uchil, Pradeep D -- Sultana, Hameeda -- Brass, Abraham L -- Adametz, Rachel -- Tsui, Melody -- Qian, Feng -- Montgomery, Ruth R -- Lev, Sima -- Mason, Peter W -- Koski, Raymond A -- Elledge, Stephen J -- Xavier, Ramnik J -- Agaisse, Herve -- Fikrig, Erol -- AI062773/AI/NIAID NIH HHS/ -- AI07526/AI/NIAID NIH HHS/ -- N01 AI500031/AI/NIAID NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- R01 AI032947/AI/NIAID NIH HHS/ -- R01 AI041440/AI/NIAID NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- U01 AI070343/AI/NIAID NIH HHS/ -- U01 AI070343-04/AI/NIAID NIH HHS/ -- U54 AI057156/AI/NIAID NIH HHS/ -- U54 AI057156-01/AI/NIAID NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- U54 AI057159-01/AI/NIAID NIH HHS/ -- U54AI057159/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Sep 11;455(7210):242-5. doi: 10.1038/nature07207.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticutt 06520-8031, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18690214" target="_blank"〉PubMed〈/a〉
    Keywords: Computational Biology ; Dengue Virus/physiology ; Endoplasmic Reticulum/metabolism ; Gene Expression Profiling ; Genome, Human ; Hiv ; HeLa Cells ; Humans ; Immunity/genetics ; Monocarboxylic Acid Transporters/deficiency/genetics/metabolism ; Muscle Proteins/deficiency/genetics/metabolism ; Protein Binding ; *RNA Interference ; Ubiquitin-Protein Ligases/deficiency/genetics/metabolism ; Ubiquitination/genetics ; Vesiculovirus ; Virus Replication ; West Nile Fever/*genetics/*virology ; West Nile virus/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-04-23
    Description: TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13-UEV1A (also known as UBE2N-UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFkappaB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13-UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-kappaB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081621/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pertel, Thomas -- Hausmann, Stephane -- Morger, Damien -- Zuger, Sara -- Guerra, Jessica -- Lascano, Josefina -- Reinhard, Christian -- Santoni, Federico A -- Uchil, Pradeep D -- Chatel, Laurence -- Bisiaux, Aurelie -- Albert, Matthew L -- Strambio-De-Castillia, Caterina -- Mothes, Walther -- Pizzato, Massimo -- Grutter, Markus G -- Luban, Jeremy -- R01 AI059159/AI/NIAID NIH HHS/ -- R01 AI059159-06/AI/NIAID NIH HHS/ -- R01AI59159/AI/NIAID NIH HHS/ -- R21 AI087467/AI/NIAID NIH HHS/ -- R21AI087467/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Apr 21;472(7343):361-5. doi: 10.1038/nature09976.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Medicine, University of Geneva, Geneva CH-1211, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21512573" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid/*chemistry/*immunology ; Carrier Proteins/genetics/*immunology/*metabolism ; Cell Line ; Enzyme Activation ; HEK293 Cells ; HIV-1/chemistry/immunology ; Humans ; Immunity, Innate/*immunology ; Lipopolysaccharides/immunology/pharmacology ; MAP Kinase Kinase Kinases/metabolism ; NF-kappa B/metabolism ; Protein Binding ; Receptors, Pattern Recognition/immunology/metabolism ; Retroviridae/chemistry/*immunology ; Signal Transduction/drug effects/immunology ; Transcription Factor AP-1/metabolism ; Transcription Factors/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/genetics/immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-10-03
    Description: Dendritic cells can capture and transfer retroviruses in vitro across synaptic cell-cell contacts to uninfected cells, a process called trans-infection. Whether trans-infection contributes to retroviral spread in vivo remains unknown. Here, we visualize how retroviruses disseminate in secondary lymphoid tissues of living mice. We demonstrate that murine leukemia virus (MLV) and human immunodeficiency virus (HIV) are first captured by sinus-lining macrophages. CD169/Siglec-1, an I-type lectin that recognizes gangliosides, captures the virus. MLV-laden macrophages then form long-lived synaptic contacts to trans-infect B-1 cells. Infected B-1 cells subsequently migrate into the lymph node to spread the infection through virological synapses. Robust infection in lymph nodes and spleen requires CD169, suggesting that a combination of fluid-based movement followed by CD169-dependent trans-infection can contribute to viral spread.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651917/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651917/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sewald, Xaver -- Ladinsky, Mark S -- Uchil, Pradeep D -- Beloor, Jagadish -- Pi, Ruoxi -- Herrmann, Christin -- Motamedi, Nasim -- Murooka, Thomas T -- Brehm, Michael A -- Greiner, Dale L -- Shultz, Leonard D -- Mempel, Thorsten R -- Bjorkman, Pamela J -- Kumar, Priti -- Mothes, Walther -- P01 AI078897/AI/NIAID NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- P50 GM082545/GM/NIGMS NIH HHS/ -- P50GM082545/GM/NIGMS NIH HHS/ -- R01 AI097052/AI/NIAID NIH HHS/ -- R01 AI112443/AI/NIAID NIH HHS/ -- R01 CA098727/CA/NCI NIH HHS/ -- R01 DA036298/DA/NIDA NIH HHS/ -- S10 RR026697/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 30;350(6260):563-7. doi: 10.1126/science.aab2749. Epub 2015 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA. sewald@mvp.uni-muenchen.de priti.kumar@yale.edu walther.mothes@yale.edu. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA. ; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA. ; Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA. ; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA. ; The Jackson Laboratory, Bar Harbor, ME 04609, USA. ; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA. sewald@mvp.uni-muenchen.de priti.kumar@yale.edu walther.mothes@yale.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26429886" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dendritic Cells/immunology/virology ; HIV Infections/*immunology ; HIV-1/*physiology ; Humans ; Leukemia Virus, Murine/*physiology ; Lymph Nodes/immunology/virology ; Lymphocytes/immunology/*virology ; Macrophages/immunology/virology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Retroviridae Infections/*immunology ; Sialic Acid Binding Ig-like Lectin 1/genetics/*physiology ; Spleen/immunology/virology ; *Virus Internalization
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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