Project area B:
Viral and cellular factors involved in RNA virus tropism and pathogenicity
B04Nipah virus replication in respiratory epithelial cells
Prof. Dr. Andrea Maisner
Institut für Virologie
Phone: 06421-28 65360
Nipah virus (NiV) is a zoonotic BSL-4-classified paramyxovirus that causes clinical infections in pigs and humans. The severity of respiratory symptoms and the frequency of virus transmission by airway secretions clearly differ in the two species. While differences in lung histopathology in tissue samples obtained from NiV-infected pigs and humans have been described, comparative studies on productive NiV replication in organ cultures and primary airway epithelial cells of the two species were lacking. During the previous funding period, the Maisner group was able to define species-specific host factors that influence virus replication by comparing NiV infection in primary bronchial epithelial cultures obtained from both species. The group demonstrated that NiV receptor expression levels are important determinants of the differences in NiV replication kinetics in primary porcine and human respiratory epithelial cells. The studies further revealed that NiV replication kinetics and ephrin-B2 receptor levels not only differ between airway cells from pigs and humans (species-specific variability), but also between cells from different human donors (individual variations). Most recently, the Maisner group discovered that NiV infection of porcine and human airway epithelia poorly induced IFN-ß but caused a substantial upregulation of the type III interferon IFN-λ.Project-related publications of the investigator:
- Elvert M, Sauerhering L, & Maisner A (2020). Cytokine induction in Nipah virus-infected primary human and porcine bronchial epithelial cells. J Infect Dis 221: S395-400.
- Ringel M, Behner L, Heiner A, Sauerhering L, & Maisner A (2020). Replication of a Nipah virus encoding a nuclear-retained matrix protein. J Infect Dis 221: S389-394.
- Hoffmann M, Nehlmeier I, Brinkmann C, Krähling V, Behner L, Moldenhauer AS, Krüger N, Nehls J, Schindler M, Hoenen T, Maisner A, Becker S#, & Pöhlmann S (2019). Tetherin inhibits Nipah virus but not Ebola virus replication in fruit bat cells. J Virol 93: e01821-18.
- Ringel M, Heiner A, Behner L, Halwe S, Sauerhering L, Becker N, Dietzel E, Sawatsky B#, Kolesnikova L#, & Maisner A (2019). Nipah virus induces two inclusion body populations: Identification of novel inclusions at the plasma membrane. PLoS Pathog 15(4): e1007733.
- Behner L, Zimmermann L, Ringel M, Weis M, & Maisner A (2018). Formation of high-order oligomers is required for functional bioactivity of an African bat henipavirus surface glycoprotein. Vet Microbiol. 218: 90-97.
- Sauerhering L, Müller H, Behner L, Elvert M, Fehling SK, Strecker T#, & Maisner A (2017). Variability of interferon-λ induction and antiviral activity in Nipah virus infected differentiated human bronchial epithelial cells of two human donors. J Gen Virol 98(10):2447-2453.
- Sauerhering L, Zickler M, Elvert M, Behner L, Matrosovich T, Erbar S, Matrosovich M#, & Maisner A (2016). Species-specific and individual differences in NiV replication in porcine and human airway epithelial cells. J Gen Virol. 97(7): 1511-1519.
B05Lassa virus: host cell tropism and molecular pathogenesis
Dr. Thomas Strecker
Institut für Virologie
Phone: 06421-28 65182
Lassa virus (LASV) is a zoonotic, hemorrhagic fever-causing virus that is endemic to West Africa. Approved vaccines or specific antiviral drugs suitable to combat these infections are not available. The primary transmission route of LASV from its reservoir host to humans involves direct exposure to virus-containing rodent excretions. Although the initial infection involves the respiratory tract through inhalation of contaminated dust or fomites, information on LASV infection of human respiratory epithelial cells is limited. In the current funding period, the Strecker group observed that LASV infects polarized bronchial epithelial cells via the apical or basolateral side, while progeny virus particles are released predominantly from the apical surface. Goblet cells and basal cells were identified as initial LASV target cells in a primary human bronchial epithelial cell culture model. Together with collaborators, the Strecker group also solved the three-dimensional architecture of LASV virions and the spike envelope glycoprotein using high-resolution electron cryomicroscopy and tomography techniques.Project-related publications of the investigator:
- Müller H, Fehling SK, Dorna J, Urbanowicz RA, Oestereich L, Krebs Y, Kolesnikova L, Schauflinger M, Krahling V, Magassouba N, Fichet-Calvet E, Ball JK, Kaufmann A, Bauer S, Becker S, von Messling V, Strecker T. 2020. Adjuvant formulated virus-like particles expressing native-like forms of the Lassa virus envelope surface glycoprotein are immunogenic and induce antibodies with broadly neutralizing activity. NPJ Vaccines 5:71.
- Blok AJ, Gurnani P, Xenopoulos A, Burroughs L, Duncan J, Urbanowicz RA, Tsoleridis T, Müller-Kräuter H, Strecker T, Ball JK, Alexander C, Alexander MR. 2020. Polymer microarrays rapidly identify competitive adsorbents of virus-like particles. Biointerphases. 17;15(6):061005.
- Olayemi A, Adesina AS, Strecker T, Magassouba N, Fichet-Calvet E. 2020. Determining Ancestry between Rodent- and Human-Derived Virus Sequences in Endemic Foci: Towards a More Integral Molecular Epidemiology of Lassa Fever within West Africa. Biology (Basel) 9.
- Thom R#, Tipton T#, Strecker T#, Hall Y#, Akoi Bore J#, et al. 2020. Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study. Lancet Infect Dis 30736-2. #joint first authorship
- Timothy JWS, Hall Y, Akoi-Bore J, Diallo B, Tipton TRW, Bower H, Strecker T, Glynn JR, Carroll MW. 2019. Early transmission and case fatality of Ebola virus at the index site of the 2013-16 west African Ebola outbreak: a cross-sectional seroprevalence survey. Lancet Infect Dis 19:429-438.
- Whitmer SLM#, Strecker T#, Cadar D#, et al. 2018. New Lineage of Lassa Virus, Togo, 2016. Emerg Infect Dis 24:599-602. #joint first authorship
- Watanabe Y, Raghwani J, Allen JD, Seabright GE, Li S, Moser F, Huiskonen JT, Strecker T, Bowden TA, Crispin M. 2018. Structure of the Lassa virus glycan shield provides a model for immunological resistance. Proc Natl Acad Sci U S A 115:7320-7325.
- Sauerhering L, Müller H, Behner L, Elvert M, Fehling SK, Strecker T, Maisner A. 2017. Variability of interferon-lambda induction and antiviral activity in Nipah virus infected differentiated human bronchial epithelial cells of two human donors. J Gen Virol 98:2447-2453.
- Huber M, Suprunenko T, Ashhurst T, Marbach F, Raifer H, Wolff S, Strecker T, Viengkhou B, Jung SR, Obermann HL, Bauer S, Xu HC, Lang PA, Tom A, Lang KS, King NJC, Campbell IL, Hofer MJ. 2017. IRF9 Prevents CD8(+) T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection. J Virol 91.
B06Functional comparison of the NSs virulence factors from the genus Phlebovirus
Prof. Dr. Friedemann Weber
Institut für Virologie
Phone: 0641-99 38350
The genus Phlebovirus (family Phenuiviridae, order Bunyavirales) contains virus species covering a wide spectrum of virulence. Rift Valley fever virus (RVFV) is highly pathogenic representative, whereas the Sandfly fever Sicilian virus (SFSV) displays an intermediate level of virulence. Although the importance of phleboviruses is increasingly recognized, we are only beginning to understand the mechanisms of pathogenicity. A key virulence factor of phleboviruses is the non-structural protein NSs, an inhibitor of the antiviral type I interferon (IFN) system. In the previous two funding periods, the Weber group identified the mechanisms by which the NSs proteins of both RVFV and SFSV inhibit the transactivation of the IFN genes and abrogate the antiviral protein kinase R (PKR) pathway. For RVFV, the NSs was found to recruit several E3 ubiquitin ligases of the F-Box type in order to destroy the general host cell transcription factor TF-IIH and the antiviral mRNA translation inhibitor PKR. SFSV NSs, by contrast, is occluding the DNA-binding domain of the IFN transcription factor IRF-3 to inhibit IFN induction, and also binds to the translation initiation factor eIF2B to protect the ribosomal machinery against the inhibitory PKR signaling. Expectedly, phleboviruses with a deleted NSs gene are strong activators of the IFN system. Using an NSs-deleted RVFV, the viral panhandle was identified the main trigger of IFN induction, RIG-I as its cytoplasmic sensor, and the full set of upregulated innate immunity genes was characterized by transcriptome analysis.Project-related publications of the investigator:
- Kashiwagi, K., Y. Shichino, T. Osaki, A. Sakamoto, M. Nishimoto, M. Takahashi, M. Mito, F Weber, Y. Ikeuchi, S. Iwasaki, and T. Ito (2021): eIF2B-capturing viral protein NSs suppresses the integrated stress response (2021): Nature Communications 12, Article number: 7102
- Wuerth, J.D., Weber (2021): NSs of the mildly virulent sandfly fever Sicilian virus is unable to inhibit interferon signaling and upregulation of interferon-stimulated genes. J. Gen. Virol. 102(11). doi: 10.1099/jgv.0.001676
- Wuerth, J.D., M. Habjan, M. Kainulainen, B. Berisha, D. Bertheloot, G. Superti-Furga, A. Pichlmair, Weber (2020): eIF2B as target for viral evasion of PKR-mediated translation inhibition. mBio 11, pii: e00976-20, doi: 10.1128/mBio.00976-20
- Schoen, A., S. Lau, P. Verbruggen, Weber (2020): Elongin C contributes to RNA polymerase II degradation by the interferon antagonist NSs of La Crosse orthobunyavirus. J. Virol. 4: e02134-19
- Barr, J.D., Weber, C. S. Schmaljohn (2020): Bunyaviruses. Chapter 17, Fields Virology, 7th edition. Lippincott Williams & Wilkins – Philadelphia, USA, in press
- Hölzer, M., A. Schoen, J. Wulle, M. A. Müller, C. Drosten, M. Marz*, Weber* (2019): Virus- and interferon alpha-induced transcriptomes of cells from the microbat Myotis daubentonii. iScience, 19, 647–661
- Lau, S., Weber (2019): Nuclear pore protein Nup98 is involved in replication of Rift Valley fever virus and nuclear import of virulence factor NSs. J. Gen. Virol. DOI 10.1099/jgv.0.001347
- Wuerth, J.D., Weber (2019): Ferreting out virus pathogenesis. Nat. Microbiol. 4: 384-385
- Jones, R., S. Lessoued, K. Meier, S. Devignot, S. Barata, M. Mate, G. Bragagnolo, Weber, M. Rosenthal, J. Reguera (2019): Structure and function of the Toscana virus cap-snatching endonuclease. Nucleic Acids Research 47: 10914–10930, doi: 10.1093/nar/gkz838
- Frantz, R., L. Teubner, T. Schultze, L. La Pietra, C. Müller, K. Gwozdzinski, H. Pillich, T. Hain, M. Weber-Gerlach, G.-D. Panagiotidis, A. Mostafa, Weber, M. Rohde, S. Pleschka, T. Chakraborty, M. A. Mraheil (2019): The secRNome of Listeria monocytogenes harbors small non-coding RNAs that are potent inducers of IFN-β. mBio 10, pii: e01223-19
- Wuerth J.D., M. Habjan, J. Wulle, G. Superti-Furga, A. Pichlmair, Weber (2018). NSs protein of Sandfly fever Sicilian phlebovirus counteracts interferon induction by masking the DNA-binding domain of interferon regulatory factor 3. J. Virol. 92: e01202-18
- Kiening, M., Weber, D. Frishman (2017): Conserved RNA structures in the intergenic regions of ambisense viruses. Scientific Reports, Article number: 16625
- Ferron, F, Weber, J. C. de la Torre, J. Reguera (2017): Transcription and replication mechanisms of Bunyaviridae and Arenaviridae L proteins. Virus Research 234:118-134
B07The protease specificity of influenza virus hemagglutinin and coronavirus spike protein with monobasic cleavage site: underlying mechanisms and host proteases involved
Prof. Dr. Eva Böttcher-Friebertshäuser
Institut für Virologie
Phone: 06421-28 66019
Proteolytic cleavage of the surface glycoprotein hemagglutinin (HA) of influenza A virus is essential for virus infectivity and spread, and the host cell proteases responsible for this cleavage are promising new drug targets. The Böttcher-Friebertshäuser group identified TMPRSS2 (transmembrane protease serine S1 member 2) and HAT/TMPRSS11D (human airway trypsin-like protease) as human proteases that cleave HA with a monobasic cleavage site in vitro. More recent studies demonstrated that TMPRSS2 is essential for pneumotropism and pathogenesis of H1N1 and H7N9 influenza virus in mice, whereas activation and spread of H3N2 virus into the lung was independent of TMPRSS2 expression. It is thus becoming increasingly clear that HA activation in the respiratory tract is much more complex than previously thought: influenza viruses can differ in their sensitivity to different host cell proteases and the availability of appropriate proteases can vary along the respiratory tract and even in different target cells. This project aims to i) identify the unknown H3-activating protease(s) in mice, ii) validate the protease specificity of HA proteins with monobasic cleavage sites in human respiratory epithelial cells and iii) gain insights into the mechanisms underlying the protease specificity of HA by investigating proteolytic activation of further HA subtypes in TMPRSS2-knockout mice. In addition, the roles of cell tropism and/or virus-induced host responses affecting the protease specificity for different HA subtypes will be analyzed.Project-related publications of the investigator:
- Harbig A, Mernberger M, Bittel L, Pleschka S, Schughart K, Steinmetzer T, Stiewe T, Nist A, Böttcher-Friebertshäuser E. 2020. Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airway. J Biol Chem. 295:11388-407.
- Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, Stein DA, Hardes K, Eickmann M, Dolnik O, Rohde C, Klenk HD, Garten W, Steinmetzer T, Böttcher-Friebertshäuser E. 2020. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Science Alliance. 3(9), e202000786.
- Limburg H, Harbig A, Bestle D, Stein DA, Moulton HM, Jaeger J, Janga H, Hardes K, Koepke J, Schulte L, Koczulla AR, Schmeck B, Klenk HD, Böttcher-Friebertshäuser E. 2019. TMPRSS2 is the major activating protease of influenza A virus in primary human airway cells and influenza B virus in human type II pneumocytes. J Virol. 93: pii: e00649-19.
- Tarnow C, Engels G, Arendt A, Schwalm F, Sediri H, Preuss A, Nelson PS, Garten W, Klenk HD, Gabriel G, Böttcher-Friebertshäuser E. 2014. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol. 88:4744-51.
- Baron J, Tarnow C, Mayoli-Nüssle D, Schilling E, Meyer D, Hammami M, Schwalm F, Steinmetzer T, Guan Y, Garten W, Klenk HD, Böttcher-Friebertshäuser E. 2013. Matriptase, HAT and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol. 87:1811-20.
- Böttcher-Friebertshäuser E, Lu Y, Meyer D, Sielaff F, Steinmetzer T, Klenk HD, Garten W. 2012. Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections. Vaccine 30:7374-80.
- Böttcher-Friebertshäuser E, Stein DA, Klenk HD, Garten W. 2011. Inhibition of influenza virus infection in human airway cell cultures by an antisense peptide-conjugated morpholino oligomer targeting the hemagglutinin-activating protease TMPRSS2. J Virol 85:1554-62.
- Böttcher-Friebertshäuser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J, Steinmetzer T, Klenk HD, Garten W. 2010. Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol 84:5605-14.
- Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M. 2006. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80:9896-8.
B08Structural and functional factors determining entry and replication of hepatitis D and B viruses during co-infection
Dieter Glebe, Joachim Geyer
Prof. Dr. Dieter Glebe
Institut für Medizinische Virologie
Phone: 0641-99 41246
Prof. Dr. Joachim Geyer
Institut für Pharmakologie und Toxikologie
Phone: 0641-99 38404
Hepatitis D virus (HDV) is an enveloped virus containing a small single-stranded circular RNA genome with a viroid-like replication mechanism. HDV can cause acute and chronic liver disease resulting in liver cirrhosis and liver cancer. HDV is a defective virus requiring the presence of hepatitis B virus (HBV) in the same hepatocyte to complete its life cycle. HDV superinfection of chronic hepatitis B patients severely worsens their clinical outcome, although active HDV replication usually leads to an overall suppression of replication and secretion of the coinfecting HBV. In 2012, the liver-specific and differentiation-dependent bile acid (BA) transporter NTCP (Na+/taurocholate co-transporting polypeptide) was identified as a highly species- and organ-specific receptor for HBV and HDV. The Glebe and Geyer groups confirmed this discovery soon after and established (by NTCP transfection) human hepatocyte cell lines, which are highly susceptible for HBV and HDV. This experimental system enables investigation of the influence of HDV coinfection on HBV infection at the cellular level in detail. The project plans to (i) analyze direct effects of HDV infection on HBV replication in coinfected cells, (ii) dissect the role of the two HDV-encoded proteins S-HDAg and L-HDAg in the HBV infection cycle, (iii) analyze the role of ER-stress during HDV/HBV coinfection, (iv) study interactions with innate immunity/interferon stimulated genes (ISGs) under HBV/HDV coinfection/superinfection conditions and (v) investigate possible effects of HDV infection as well as L-HDAg/S-HDAg expression on NTCP expression and trafficking. Taken together, the analyses are expected to elucidate the molecular mechanisms determining the close interaction of HDV and HBV during coinfection. This might contribute to improved therapy options for chronic HDV/HBV coinfected patients by providing targets for HDV-specific therapy that is still missing.Project-related publications of the investigators:
- Lowjaga KAAT, Kirstgen M, Müller SF, Goldmann N, Lehmann F, Glebe D, Geyer J. 2020. Long-term trans-inhibition of the hepatitis B and D virus receptor NTCP by taurolithocholic acid. Am. J. Physiol. Gastronintest. Liver Physiol. Doi: 10.1152/ajpgi.00263.2020.
- Jensen O, Ansari S, Gebauer L, Müller SF, Lowjaga KAAT, Geyer J, Tzvetkov MV, Brockmöller J. 2020. A double-Flp-in method for stable overexpression of two genes. Sci. Rep. 10:14018.
- Paraskevopoulou S, Pirzer F, Goldmann N, Schmid J, Corman VM, Gottula LT, Schroeder S, Rasche A, Muth D, Drexler JF, Heni AC, Eibner GJ, Page RA, Jones TC, Müller MA, Sommer S§, Glebe D§, Drosten C§. 2020. Mammalian deltavirus without hepadnavirus coinfection in the neotropical rodent Proechimys semispinosus. Proc. Natl. Acad. Sci. U. S. A. 117(30):17977-17983. (§ shared senior authors).
- Rasche A, Lehmann F, König A, Goldmann N, Corman VM, Moreira-Soto A, Geipel A, van Riel D, Vakulenko YA, Sander AL, Niekamp H, Kepper R, Schlegel M, Akoua-Koffi C, Souza BFCD, Sahr F, Olayemi A, Schulze V, Petraityte-Burneikiene R, Kazaks A, Lowjaga KAAT, Geyer J, Kuiken T, Drosten C, Lukashev AN, Fichet-Calvet E, Ulrich RG, Glebe D§, Drexler JF§. 2019. Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses. Proc. Natl. Acad. Sci. U. S. A. 116(34):17007-17012. (§ shared senior authors)
- Noppes S, Müller SF, Bennien J, Holtemeyer M, Palatini M, Leidolf R, Alber J, Geyer J. 2019. Homo- And Heterodimerization Is a Common Feature of the Solute Carrier Family SLC10 Members. Biol. Chem. 400(10):1371-1384.
- Gerresheim GK, Bathke J, Michel AM, Andreev DE, Shalamova LA, Rossbach O, Hu P, Glebe D, Fricke M, Marz M, Goesmann A, Kiniry SJ, Baranov PV, Shatsky IN, Niepmann M. 2019. Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling. Int. J. Mol. Sci. 20(6):1321.
- Müller SF, König A, Döring B, Glebe D, Geyer J. 2018. Characterisation of the Hepatitis B Virus Cross-Species Transmission Pattern via Na+/taurocholate Co-Transporting Polypeptides From 11 New World and Old World Primate Species. PLoS One 13(6):e0199200.
- de Carvalho Dominguez Souza BF, König A, Rasche A, de Oliveira Carneiro I, Stephan N, Max Corman V, Luise Roppert P, Goldmann N, Kepper R, Franz Müller S, Völker C, Junior Souza de Souza A, Soares Gomes-Gouvêa M, Moreira-Soto A, Stöcker A, Nassal M, Roberto Franke C, Renato Rebello Pinho J, do Carmo Pereira Soares M, Geyer J, Lemey P, Drosten C, Martins Netto E, Glebe D§, Felix Drexler J§. 2018. A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses. J. Hepatol. 68(6):1114-1122. (§ shared senior authors)
- Pfefferkorn M, Böhm S, Schott T, Deichsel D, Bremer CM, Schröder K, Gerlich WH, Glebe D, Berg T, van Bömmel F. 2018. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers. Gut 67(11):2045-2053.
- Nielsen KO, Mirza AH, Kaur S, Jacobsen KS, Winther TN, Glebe D, Pociot F, Hogh B, Størling J. 2018. Hepatitis B virus suppresses the secretion of insulin-like growth factor binding protein 1 to facilitate anti-apoptotic IGF-1 effects in HepG2 cells. Exp. Cell Res. 370(2):399-408.
B10Function of lipid droplets in replication and pathogenesis of neurotropic flaviviruses
Prof. Dr. Eva Herker
Institut für Virologie
Phone: 06421-28 66019
Project-related publications of the investigator:
- Lassen S, Gruttner C, Nguyen-Dinh V, and Herker E. Perilipin-2 is critical for efficient lipoprotein and hepatitis C virus particle production. J Cell Sci 2019; 132: jcs.217042.
- Hofmann S, Krajewski M, Scherer C, Scholz V, Mordhorst V, Truschow P, Schobel A, Reimer R, Schwudke D, and Herker E. Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863: 1041-1056.
- Schobel A, Rosch K, and Herker E. Functional innate immunity restricts Hepatitis C Virus infection in induced pluripotent stem cell-derived hepatocytes. Sci Rep 2018; 8: 3893.
- Rosch K, Kwiatkowski M, Hofmann S, Schobel A, Gruttner C, Wurlitzer M, Schluter H, and Herker E. Quantitative Lipid Droplet Proteome Analysis Identifies Annexin A3 as a Cofactor for HCV Particle Production. Cell Rep 2016; 16: 3219-3231.
- Camus G, Schweiger M, Herker E, Harris C, Kondratowicz AS, Tsou CL, Farese RV, Jr., Herath K, Previs SF, Roddy TP, Pinto S, Zechner R, and Ott M. The hepatitis C virus core protein inhibits adipose triglyceride lipase (ATGL)-mediated lipid mobilization and enhances the ATGL interaction with comparative gene identification 58 (CGI-58) and lipid droplets. J Biol Chem 2014; 289: 35770-35780.
- Eggert D, Rosch K, Reimer R, and Herker E. Visualization and analysis of hepatitis C virus structural proteins at lipid droplets by super-resolution microscopy. PLoS One 2014; 9: e102511.
- Vogt DA, Camus G, Herker E, Webster BR, Tsou CL, Greene WC, Yen TS, and Ott M. Lipid droplet-binding protein TIP47 regulates hepatitis C Virus RNA replication through interaction with the viral NS5A protein. PLoS Pathog 2013; 9: e1003302.
- Camus G, Herker E, Modi AA, Haas JT, Ramage HR, Farese RV, Jr., and Ott M. Diacylglycerol acyltransferase-1 localizes hepatitis C virus NS5A protein to lipid droplets and enhances NS5A interaction with the viral capsid core. J Biol Chem 2013; 288: 9915-9923.
- Harris C, Herker E, Farese RV, Jr., and Ott M. Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis. J Biol Chem 2011; 286: 42615-42625.
- Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese RV, Jr., and Ott M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 2010; 16: 1295-1298.
B11Molecular basis for the virulence of deformed wing virus infections in honey bees
Prof. Dr. Benjamin Lamp
Institut für Virologie
Phone: 0641-99 38356
The Deformed wing virus (DWV; order Picornavirales) is a major pathogen of honey bees (Apis mellifera) and responsible for colony collapses. It is hypothesized that virulent emerging DWV strains have evolved from less virulent precursors. In this funding period, we want to decipher the molecular determinants of DWV virulence using combined molecular biological and protein biochemical approaches. Molecular markers of DWV virulence will be elucidated by studying (I) inter-strain recombination, (II) in vivo passaging and adaptation of DWV-B, and (III) the role of the viral leader protein as potential RNAi escape factor. An avirulent DWV-B will be used as a platform to localize the genomic regions responsible for virulence. (I) The series of genetically engineered DWV recombinants will be systematically studied for replication, viral titers, host cell range and virulence in honey bee pupae and primary bee cells. (II) We will passage a DWV-B clone in vivo to study virulence emergence. Responsible mutations will be characterized using reverse genetics. (III) We hypothesize that the leader protein of DWV is an antagonist of the innate immune defense of honey bees and hence a central virulence factor. We will characterize the leader protein of DWV using reporter assays, recombinant cell culture expression, and pull-down experiments to identify the interacting host cell factors. Hopefully, our results will contribute to the establishment of new concepts against the devastating colony losses in beekeeping.Project-related publications of the investigator:
- Seitz, K., K. Buczolich, A. Dikunova, P. Plevka, K. Power, T. Rumenapf, and B. Lamp* (2019). A molecular clone of Chronic Bee Paralysis Virus (CBPV) causes mortality in honey bee pupae (Apis mellifera). Scientific reports 9(1):16274, doi: 10.1038/s41598-019-52822-1
- Kiesler, A., K. Seitz, L. Schwarz, K. Buczolich, H. Petznek, E. Sassu, S. Dürlinger, S. Högler, A. Klang, C. Riedel, H.-W. Chen, M. Mötz, P. Kirkland, H. Weissenböck, A. Ladinig, T. Rümenapf, and B. Lamp* (2019). Clinical and Serological Evaluation of LINDA Virus Infections in Post-Weaning Piglets. Viruses 11, 975, doi: 10.3390/v11110975
- Riedel, C., B. Lamp, H.-W. Chen, M. Heimann, and T. Rümenapf (2019). Fluorophore labelled BVDV. A novel tool for the analysis of infection dynamics. Scientific reports 9, 5972, doi:10.1038/s41598-019-42540-z
- Lamp, B.*, L. Schwarz, S. Högler, C. Riedel, L. Sinn, B. Rebel-Bauder, H. Weissenböck, A. Ladinig, and T. Rümenapf (2017). Novel Pestivirus Species in Pigs, Austria, 2015. Emerging Infectious Diseases 23(7):1176-1179. doi:10.3201/eid2307.170163
- Schwarz, L., C. Riedel, S. Högler, L. Sinn, T. Voglmayr, B. Wöchtl, N. Dinhopl, B. Rebel-Bauder, H. Weissenböck, A. Ladinig, T. Rümenapf, and B. Lamp* (2017). Congenital infection with atypical porcine pestivirus (APPV) is associated with disease and viral persistence. Veterinary Research 48:1. DOI: 10.1186/s13567-016-0406-1
- Lamp, B.*, A. Url, K. Seitz, J. Eichhorn, C. Riedel, L. J. Sinn, S. Indik, H. Koglberger, and T. Rümenapf (2016). Construction and rescue of a molecular clone of Deformed wing virus (DWV). PLOS ONE 11(11): e0164639. DOI:10.1371/journal.pone.016463
- Schurischuster S., S. Zambanini, M. Kampel, and B. Lamp* (2016). Sensor Study for Monitoring Varroa Mites on Honey Bees (Apis mellifera). Proceedings of the Visual observation and analysis of Vertebrate And Insect Behavior, VAIB 5:11, http://homepages.inf.ed.ac.uk/rbf/VAIB16PAPERS/vaibchurischuster.pdf
- Lamp, B., C. Riedel, E. Wentz, M. Tortorici, and T. Rümenapf (2013). Autocatalytic Cleavage within Classical Swine Fever Virus NS3 Leads to a Functional Separation of Protease and Helicase. J. Virol. 87, 11872-11883, DOI:10.1128/JVI.00754-13
- Riedel C, B. Lamp, M. Heimann, M. König, S. Blome, V. Moennig, C. Schüttler, H.-J. Thiel, and T. Rümenapf (2012) The Core Protein of Classical Swine Fever Virus Is Dispensable for Virus Propagation In Vitro. PLOS Pathog 8(3): e1002598. DOI:10.1371/journal.ppat.1002598
- Lamp, B., C. Riedel, G. Roman-Sosa, M. Heimann, S. Jacobi, P. Becher, H.-J. Thiel, and T. Rümenapf (2011). Biosynthesis of classical swine fever virus nonstructural proteins. J. Virol. 85, 3607-3620. DOI:10.1128/JVI.02206-10
B12Mechanistic insights into morbillivirus-induced immunosuppression and antiviral responses
Christian Pfaller, Bevan Sawatsky
Dr. Christian Pfaller
Phone: 06103-777 442
Dr. Bevan Sawatsky
Phone: 06103-777 445
Project-related publications of the investigators:
- Ayasoufi K, Pfaller CK. 2020. Seek and hide: the manipulating interplay of measles virus with the innate immune system. Curr Opin Virol 41:18-30.
- Pfaller CK, Bloyet L-M, Donohue RC, Huff AL, Bartemes WP, Yousaf I, Urzua E, Clavière M, Zachary M, de Masson d'Autume V, Carson S, Schieferecke AJ, Meyer AJ, Gerlier D, Cattaneo R. 2020. The C protein is recruited to measles virus ribonucleocapsids by the phosphoprotein. J Virol 94:e01733-19.
- Petrova VN, Sawatsky B, Han AX, Laksono BM, Walz L, Parker E, Pieper K, Anderson CA, de Vries RD , Lanzavecchia A, Kellam P, von Messling V, de Swart RL, Russell CA. 2019. Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles. Sci Immunol 4:eaay6125.
- Donohue RC, Pfaller CK, Cattaneo R. 2019. Cyclical adaptation of measles virus quasispecies to epithelial and lymphocytic cells. To V, or not to V. PLoS Pathog 15:e1007605.
- Pfaller CK, Donohue RC, Nersisyan S, Brodsky L, Cattaneo R. 2018. Extensive editing of cellular and viral double-stranded RNA structures accounts for innate immunity suppression and the pro-viral activity of ADAR1p150. PLoS Biol 16:e2006577.
- Sawatsky B, Cattaneo R, von Messling V. 2018. Canine distemper virus spread and transmission to naive ferrets: Selective pressure on signaling lymphocyte activation molecule-dependent entry. J Virol 92:e00669-18.
- Thakkar VD, Cox RM, Sawatsky B, da Fontoura Budaszewski R, Sourimant J, Wabbel K, Makhsous N, Greninger AL, von Messling V, Plemper RK. 2018. The unstructured paramyxovirus nucleocapsid protein tail domain modulates viral pathogenesis through regulation of transcriptase activity. J Virol 92:e02064-17.
- Pfaller CK, Mastorakos GM, Matchett WE, Ma X, Samuel CE, Cattaneo R. 2015. Measles virus defective interfering RNAs are generated frequently and early in the absence of C protein and can be destabilized by adenosine deaminase acting on RNA-1-like hypermutations. J Virol 89:7735–7747.
- Pfaller CK, Radeke MJ, Cattaneo R, Samuel CE. 2014. Measles virus C protein impairs production of defective copyback double-stranded viral RNA and activation of protein kinase R. J Virol 88:456–468.
- Sawatsky B, Wong X-X, Hinkelmann S, Cattaneo R, von Messling V. 2012. Canine distemper virus epithelial cell infection is required for clinical disease but not for immunosuppression. J Virol 86:3658–3666.