{"id":5607,"date":"2019-09-11T16:17:09","date_gmt":"2019-09-11T14:17:09","guid":{"rendered":"https:\/\/www.resist-cluster.de\/?page_id=5607"},"modified":"2024-12-19T09:30:40","modified_gmt":"2024-12-19T08:30:40","slug":"project-d2","status":"publish","type":"page","link":"https:\/\/www.resist-cluster.de\/en\/research\/project-area-d\/project-d2\/","title":{"rendered":"Project D2"},"content":{"rendered":"

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What new therapeutic options open up, from research into the assembly process of herpesviruses<\/h1><\/div>

Prof. Gr\u00fcnewald\u00a0 |\u00a0 Prof. Krey\u00a0 |\u00a0 Prof. Messerle\u00a0 |\u00a0 Prof. Sodeik<\/a><\/p><\/h2><\/div>

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What is this research project about?<\/h1><\/div>
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HSV1 (red) in nerve cells (tubulin in blue)<\/p>\n<\/div>

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What is this research project about?<\/h1><\/div>

While a healthy immune system is able to control herpesviruses, primary and recurrent infections can cause severe disease; particularly very early in life and in the elderly as well as in individuals with increased susceptibility, either due to genetic factors or to immune suppression, e.g., after organ transplantation or for those living with HIV\/AIDS. Due to their ubiquitous prevalence, the disease burden of herpesviruses is high in industrialized and developing countries. Diseases range from stigmatizing skin lesions to unbearable pain, life-threatening encephalitis and cancers. The human herpesviruses responsible for the most serious and even life-threatening complications are human cytomegalovirus (HCMV), Herpes Simplex virus (HSV-1 and HSV-2), Varicella Zoster Virus (VZV), and Kaposi Sarcoma Herpesvirus (KSHV).<\/p>\n<\/div>

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What’s the current status?<\/h1><\/div>
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Only few licensed drugs are in clinical use to treat herpesvirus infections, and these target mainly enzymes required for viral DNA replication. Furthermore, these drugs have severe side effects, and resistant viral strains emerge upon prolonged treatment. The recently approved Letermovir that inhibits the HCMV terminase, may represent the first drug to expand our scope of antiviral targets. However, first resistant HCMV mutants have already been described indicating that combination therapies \u2013 as used successfully against HIV and HCV \u2013 are required. To this end, our research aims at the identification and characterization of unique protein-protein interactions that are essential for virion assembly and therefore potentially represent novel druggable targets. This strategy will pave the way for advanced combination therapies with reduced side effects, and a much lower risk of the emergence of drug-resistant viruses in patients.<\/p>\n<\/div>

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What are the project goals?<\/h1><\/div>

The major aims of this project are to characterize novel molecular mechanisms and protein-protein interactions that are key for herpesvirus assembly. The latter is a complex and highly regulated process including nuclear capsid assembly and genome packaging, nuclear egress, tegumentation in the cytoplasm, and capsid envelopment on cytoplasmic organelles. Each of these steps relies on essential, highly conserved, multimeric protein-protein interactions. Herpesvirus capsids assemble in the nucleus followed by genome packaging \u2013 a process mediated by a viral ternary protein complex called \u201cterminase\u201d. Subsequently, the mature capsids exit the nucleus via a specific nuclear escape mechanism that is driven by a viral protein complex called \u201cnuclear egress complex\u201d. Interactions of inner tegument proteins with the host cell\u2019s microtubule transport machinery facilitate capsid transport to the site of final envelopment. We aim to synergize our diverse expertise on herpesvirus cell biology, protein functions, and structure to identify crucial protein-protein interactions that provide unique targets for novel anti-herpesviral therapy.<\/p>\n<\/div><\/div><\/div>

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How do we get there?<\/h1><\/div>
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We will focus on elucidating the underlying molecular principles how evolutionary conserved protein complexes function in herpesvirus assembly, and unite our unique expertise on crucial steps of herpesviral assembly (in collaboration with Thomas Schulz and Abel Viejo Borbolla). Combined, we have profound experience on sophisticated protein expression strategies, state-of-the-art structural biology (including X-ray crystallography, cryo electron microscopy, and electron cryo tomography), protein biochemistry (e.g. label-free interaction analysis, co-immuno-precipitation, in vitro capsid assembly and tegumentation), herpesvirus genetics (BAC mutagenesis), immunoelectron microscopy of infected cells and tissues, and life cell imaging using strains with fluorescently tagged capsids and tegument. With our broad expertise, we will uncover evolutionarily conserved mechanisms as well as steps that diverge in virus assembly among different herpesviruses.<\/p>\n<\/div>

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Projectleaders D2<\/h1><\/div>

Project title: Herpesviral assembly<\/h4><\/div>
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Prof. Dr. Kay Gr\u00fcnewald<\/h3><\/div>

Projects: D1<\/a>, D2<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Prof. Dr. Thomas Krey<\/h3><\/div>

Projects: B10<\/a>, D1<\/a>, D2<\/a><\/h3><\/div>
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CV & Contact<\/span><\/a><\/div>
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Prof. Dr. Martin Messerle<\/h3><\/div>

Projects: D1<\/a>, D2<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Prof. Dr. Beate Sodeik<\/h3><\/div>

Projects: A4<\/a>, D1<\/a>, D2<\/a><\/h3><\/div>
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CV & VIDEO<\/span><\/a><\/div>
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Project D2 Publications<\/h1><\/div>

Publications 2024<\/strong><\/p>\n

Molecular plasticity of herpesvirus nuclear egress analysed in situ.<\/strong>\u00a0<\/a>Pra\u017e\u00e1k V, Mironova Y, Vasishtan D, Hagen C, Laugks U, Jensen Y, Sanders S, Heumann JM, Bosse JB, Klupp BG, Mettenleiter TC, Grange M, Gr\u00fcnewald K. Nat Microbiol. 2024 Jul;9(7):1842-1855.<\/p>\n

Viral modulation of type II interferon increases T cell adhesion and virus spread.<\/strong><\/a> Jacobsen C, Pl\u00fcckebaum N, Ssebyatika G, Beyer S, Mendes-Monteiro L, Wang J, Kropp KA, Gonz\u00e1lez-Motos V, Steinbr\u00fcck L, Ritter B, Rodr\u00edguez-Gonz\u00e1lez C, B\u00f6ning H, Nikolouli E, Kinchington PR, Lachmann N, Depledge DP,\u00a0Krey T, Viejo-Borbolla A.Nat Commun. 2024 Jun 22;15(1):5318.<\/p>\n

MX2 forms nucleoporin-comprising cytoplasmic biomolecular condensates that lure viral capsids<\/strong>.<\/a> Moschonas GD, Delhaye L, Cooreman R, H\u00fcsers F, Bhat A, Stylianidou Z, De Bousser E, De Pryck L, Grzesik H, De Sutter D, Parthoens E, De Smet AS, Maciejczuk A, Lippens S, Callewaert N, Vandekerckhove L, Debyser Z, Sodeik B, Eyckerman S, Saelens X. Cell Host Microbe. 2024 Oct 9;32(10):1705-1724.e14.<\/p>\n

A Hitchhiker’s Guide Through the Cell: The World According to the Capsids of Alphaherpesviruses<\/strong><\/a>. D\u00f6hner K, Serrero MC, Viejo-Borbolla A, Sodeik B. Annu Rev Virol. 2024 Sep;11(1):215-238. Epub 2024 Aug 30.<\/p>\n

Herpes simplex virus type 1 modifies the protein composition of extracellular vesicles to promote neurite outgrowth and neuroinfection<\/strong><\/a>. Sun G, Kropp KA, Kirchner M, Pl\u00fcckebaum N, Selich A, Serrero M, Dhingra A, Cabrera JR, Ritter B, Bauerfeind R, Wyler E, Landthaler M, Schambach A, Sodeik B, Mertins P, Viejo-Borbolla A.mBio. 2024 Feb 14;15(2):e0330823. Epub 2024 Jan 26.<\/p>\n

Publications 2023<\/strong><\/p>\n

Targeted mutagenesis of the herpesvirus fusogen central helix captures transition states<\/strong><\/a>.\u00a0Zhou M, Vollmer B, Machala E, Chen M, Gr\u00fcnewald K, Arvin AM, Chiu W, Oliver SL. Nat Commun. 2023 Dec 2;14(1):7958.<\/p>\n

Viral determinants influencing intra- and intercellular communication in cytomegalovirus infection<\/strong><\/a>. Szymanska-de Wijs K, Dezeljin M, Bogdanow B, Messerle M.Curr Opin Virol. 2023 Jun;60:101328. doi: 10.1016\/j.coviro.2023.101328. Epub 2023 Apr 7.PMID: 37031486 Review.<\/p>\n

Imaging cytomegalovirus infection and ensuing immune responses.<\/strong><\/a> Bo\u0161njak B, Lueder Y,\u00a0Messerle M, F\u00f6rster R.Curr Opin Immunol. 2023 Jun;82:102307. doi: 10.1016\/j.coi.2023.102307. Epub 2023 Mar 28.PMID:\u00a036996701\u00a0Review.<\/p>\n

The role of nuclear pores and importins for herpes simplex virus infection.<\/strong><\/a> D\u00f6hner K, Serrero MC, Sodeik B. Curr Opin Virol. 2023 Oct;62:101361. Epub 2023 Sep 4. PMID: 37672874 Review.<\/p>\n

Publications 2022<\/strong><\/p>\n

A Unique Role of the Human Cytomegalovirus Small Capsid Protein in Capsid Assembly.<\/strong> <\/a>Borst EM, Harmening S, Sanders S, Caragliano E, Wagner K, Lenac Rovi\u0161 T, Jonji\u0107 S, Bosse JB, Messerle M. mBio. 2022 Oct 26;13(5):e0100722. Epub 2022 Sep 6.<\/p>\n

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses eLife.<\/strong><\/a> Manutea C Serrero, Virginie Girault, Sebastian Weigang, Todd M Greco, Ana Ramos Nascimento, Fenja Anderson, Antonio Piras, Ana Hickford Martinez, Jonny Hertzog, Anne Binz, Anja Pohlmann, Ute Prank, Jan Rehwinkel, Rudolf Bauerfeind, Ileana M Cristea, Andreas Pichlmair, Georg Kochs, Beate Sodeik (2022). eLife<\/p>\n

Human cytomegalovirus forms phase-separated compartments at viral genomes to facilitate viral replication.<\/strong> <\/a>Caragliano E, Bonazza S, Frascaroli G, Tang J, Soh TK, Gr\u00fcnewald K, Bosse JB, Brune W. Cell Rep. 2022 Mar 8;38(10):110469.<\/p>\n

Intermittent bulk release of human cytomegalovirus.<\/strong><\/a>\u00a0Flomm FJ, Soh TK, Schneider C, Wedemann L, Britt HM, Thalassinos K, Pfitzner S, Reimer R, Gr\u00fcnewald K, Bosse JB. PLoS Pathog. 2022 Aug 4;18(8):e1010575.<\/p>\n

Publications 2021<\/strong><\/p>\n

Assembly of infectious Kaposi\u2019s sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer.<\/strong>\u00a0<\/a>Naniima P, Naimo E, Koch S, Curth U, Alkharsah KR, Str\u00f6h LJ, Binz A, Beneke JM, Vollmer B, B\u00f6ning H, Borst EM, Desai P, Bohne J, Messerle M, Bauerfeind R, Legrand P, Sodeik B, Schulz TF, Krey T. PLoS Biol. 2021 Nov 4;19(11):e3001423.<\/p>\n

Infection-induced chromatin modifications facilitate translocation of herpes simplex virus capsids to the inner nuclear membrane.<\/strong>\u00a0<\/a>Aho V, Salminen S, Mattola S, Gupta A, Flomm F, Sodeik B, Bosse JB, Vihinen-Ranta M.PLoS Pathog. 2021 Dec 15;17(12):e1010132.<\/p>\n

Concatemeric Broccoli reduces mRNA stability and induces aggregates<\/strong><\/a>.<\/strong> Rink MR, Baptista MAP, Flomm FJ, Hennig T, Whisnant AW, Wolf N, Seibel J, D\u00f6lken L, Bosse JB. PLoS One. 2021 Aug 4;16(8):e0244166.\u00a0 eCollection 2021.<\/p>\n

Publications 2020<\/strong><\/p>\n

The prefusion structure of herpes simplex virus glycoprotein B.<\/a><\/strong> Vollmer B, Pra\u017e\u00e1k V, Vasishtan D, Jefferys EE, Hernandez-Duran A, Vallbracht M, Klupp BG, Mettenleiter TC, Backovic M, Rey FA, Topf M, Gr\u00fcnewald K.\u00a0 Sci Adv. 2020 Sep 25;6(39):eabc1726.<\/p>\n

A molecular pore spans the double membrane of the coronavirus replication organelle<\/a><\/strong>. Wolff G, Limpens RWAL, Zevenhoven-Dobbe JC, Laugks U, Zheng S, de Jong AWM, Koning RI, Agard DA, Gr\u00fcnewald K, Koster AJ, Snijder EJ, B\u00e1rcena M. Science. 2020 Sep 11;369(6509):1395-1398. doi: 10.1126\/science.abd3629. Epub 2020 Aug 6.<\/p>\n

Publications 2019<\/strong><\/p>\n

Quantitative Microscopy Reveals Stepwise Alteration of Chromatin Structure during Herpesvirus Infection.<\/strong>\u00a0<\/a>Aho V, M\u00e4ntyl\u00e4 E, Ekman A, Hakanen S, Mattola S, Chen JH, Weinhardt V, Ruokolainen V, Sodeik B, Larabell C, Vihinen-Ranta M. Viruses. 2019 Oct 11;11(10):935. doi: 10.3390\/v11100935. PMID: 31614678; PMCID: PMC6832731.<\/p>\n<\/div>

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Publications of the Project D2<\/h1><\/div>
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