• Projects

Project area B:

Viral and cellular factors involved in RNA virus tropism and pathogenicity

Principal investigator:

Prof. Dr. John Ziebuhr

Institut für Medizinische Virologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 41200
E-Mail: john.ziebuhr(at)viro.med.uni-giessen(dot)de


Research area: Molecular Virology 

Feline coronaviruses (FCoVs) are highly prevalent in the cat population and classified into two biotypes: feline enteric coronavirus (FECV) leads to inapparent persistent infections of the gut, whereas feline infectious peritonitis virus (FIPV) causes a systemic disease with fatal outcome. According to the "internal mutation theory", FIPV evolves from FECV by acquiring biotype-changing mutations, which is thought to occur in 5–10% of persistently infected cats. To date, the genetic changes responsible for the biotype switch have not been identified. The unambiguous identification of mutations critically involved in this process requires reverse genetics approaches suitable to produce, characterize, and manipulate genetically defined pairs of FECV-FIPV. The development of reverse genetic systems for FCoV field viruses represents a major technical challenge because these viruses do not grow in standard cell culture systems. In the first CRC 1021 funding period, the Tekes and Ziebuhr groups have resolved this problem and managed to establish reverse genetic systems suitable to produce wild-type and genetically manipulated serotype I field viruses, which will now be employed to identify mutations that contribute to the development of feline infectious peritonitis using both in vitro and in vivo experiments and to study functions of virus-encoded "accessory" proteins in viral pathogenesis.

Project-related publications of the investigators:
  • Lemmermeyer T, Lamp B, Schneider R, Ziebuhr J, Tekes G, Thiel HJ. 2016. Characterization of monoclonal antibodies against feline coronavirus accessory protein 7b. Vet Microbiol 184: 11-19.
  • Thiel V, Thiel HJ, Tekes G. 2014. Tackling feline infectious peritonitis via reverse genetics. Bioengineered 5: 396-400.
  • Bank-Wolf B, Stallkamp I, Wiese S, Moritz A, Tekes G, Thiel HJ. 2014. Mutations of 3c and spike protein genes correlate with the occurrence of feline infectious peritonitis. Vet Microbiol 173: 177-188.
  • Madhugiri R, Fricke M, Marz M, Ziebuhr J. 2014. RNA structure analysis of alphacoronavirus terminal genome regions. Virus Res 194: 76-89.
  • de Groot, R. J., S. C. Baker, R. Baric, L. Enjuanes, A. E. Gorbalenya, K. V. Holmes, S. Perlman, L. Poon, P. J. M. Rottier, P. J. Talbot, P. C. Y. Woo, and J. Ziebuhr. 2012. FamilyCoronaviridae, p. 806-828. In A. M. Q. King, M. J. Adams, E. B. Carstens, and E. J. Lefkowitz (ed.), Virus Taxonomy. Elsevier, Amsterdam.
  • Tekes, G., D. Spies., B. Bank-Wolf, V. Thiel and H.-J. Thiel. 2012. A reverse genetic approach to study feline infectious peritonitis. J Virol., JVI.00023-12 [pii], 10.1128/JVI.00023-12.
  • 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. 84: 3607-3620.
  • Züst, R., L. Cervantes-Barragan, M. Habjan, R. Maier, B.W. Neuman, J. Ziebuhr, K.J. Szretter, S.C. Baker, W.  Barchet, M.S. Diamond, S.G. Siddell, B. Ludewig, and V. Thiel. 2011. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nature Immunol. 12: 137-143.
  • Tekes, G., R. Hofmann-Lehmann, B. Bank-Wolf, R. Maier, H.-J. Thiel and V. Thiel. 2010. Chimeric feline coronaviruses that encode type II spike protein on type I genetic background display accelerated viral growth and altered receptor usage. J. Virol. 84: 1326-1333.
  • Tekes, G., R. Hofmann, I. Stallkamp, V. Thiel and H.-J. Thiel. 2008. Genome organization and reverse genetic analysis of a type I feline coronavirus. J. Virol. 82: 1851-1859.
  • Ziebuhr, J. 2008. Coronavirus replicative proteins, p. 65-81. In S. Perlman, T. Gallagher, and E. J. Snijder (ed.), Nidoviruses. ASM Press, Washington, DC.
  • Putics, A., A. E. Gorbalenya, and J. Ziebuhr. 2006. Identification of protease and ADP-ribose 1''-monophosphatase activities associated with transmissible gastroenteritis virus non-structural protein 3. J. Gen. Virol. 87: 651-656.
  • Minskaia, E., T. Hertzig, A.E. Gorbalenya, V. Campanacci, C. Cambillau, B. Canard, J. Ziebuhr. 2006. Discovery of an RNA virus 3'-5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. USA 103: 5108-5113.
  • Putics, A., W. Filipowicz, J. Hall, A.E. Gorbalenya, and J. Ziebuhr. 2005. ADP-ribose-1"-monophosphatase: a conserved coronavirus enzyme that is dispensable for viral replication in tissue culture. J. Virol. 79: 12721-12731.
  • Ivanov, K. A., T. Hertzig, M. Rozanov, S. Bayer, V. Thiel, A. E. Gorbalenya, and J. Ziebuhr. 2004. Major genetic marker of nidoviruses encodes a replicative endoribonuclease. Proc. Natl. Acad. Sci. USA 101: 12694-12699.
  • Conzelmann, K.-K., N. Visser, P. v. Woensel, H.-J.Thiel. 1993. Molecular characterization of porcine reproductive and respiratory syndrome virus, a member of the arterivirus group. Virology 193: 329-339.
Principal investigator:

Dr. Mikhail Matrosovich

Institut für Virologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 65166
E-Mail: matrosov(at)staff.uni-marburg(dot)de


Principal investigator:

Prof. Dr. Stefan Bauer

Institut für Immunologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 66492
E-Mail: stefan.bauer(at)staff.uni-marburg(dot)de


Research area: Molecular Virology/Molecular Immunology

Humans can be infected by seasonal, pandemic, and zoonotic influenza A viruses (IAVs). The hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of these viruses vary substantially depending on viral host species, evolutionary lineage, and strain. The long-term goal of the project is to characterize how this genetic variation affects viral replication, host range, and pathogenicity. During the first funding period, a large panel of fully characterized recombinant IAVs were generated and used to study effects of HA receptor specificity and membrane fusion activity on viral tropism to epithelial and endothelial cells and sensitivity to antiviral innate immune factors. The Matrosovich group found that the pH optimum of HA-mediated membrane fusion in specific IAVs affects their sensitivity to an interferon-induced antiviral state, and that the high pH fusion pH optimum seen in zoonotic H5N1 and H7N9 viruses is responsible for their enhanced tropism to human endothelial cells. Furthermore, the group discovered that adaptation of avian influenza viruses to pigs under natural conditions requires HA mutations that increase the fusion pH optimum. Finally, preliminary evidence was obtained to suggest a role of viral receptor specificity in IAV interactions with human alveolar macrophages and plasmacytoid dendritic cells.

Project-related publications of the principal investigators:
  • Gerlach T, Hensen L, Matrosovich T, Bergmann J, Winkler M, Peteranderl C, Klenk HD, Weber F, Herold S, Pöhlmann S, Matrosovich M. 2017. pH-optimum of hemagglutinin-mediated membrane fusion determines sensitivity of influenza A viruses to the interferon-induced antiviral state and IFITMs. J. Virol., accepted
  • Gambaryan AS, Matrosovich MN. 2015. What adaptive changes in hemagglutinin and neuraminidase are necessary for emergence of pandemic influenza virus from its avian precursor? Biochemistry (Moscow) 80:872-880.
  • Baumann J, Kouassi NM, Foni E, Klenk HD, Matrosovich M. 2015. H1N1 swine influenza viruses differ from avian precursors by a higher pH optimum of membrane fusion. J Virol 90:1569-1577.
  • Wendel I, Rubbenstroth D, Doedt J, Kochs G, Wilhelm J, Staeheli P, Klenk HD, Matrosovich M. 2015. The avian-origin PB1 gene segment facilitated replication and transmissibility of the H3N2/1968 pandemic influenza virus. J Virol 89:4170-4179.
  • Wendel I, Matrosovich M, Klenk HD. 2015. SnapShot: Evolution of Human Influenza A Viruses. Cell Host & Microbe 17:416-416.e411.
  • Heider A, Mochalova L, Harder T, Tuzikov A, Bovin N, Wolff T, Matrosovich M, Schweiger B. 2015. Alterations in hemagglutinin receptor-binding specificity accompany the emergence of highly pathogenic avian influenza viruses. J Virol 89:5395-5405.
  • Van Poucke S, Doedt J, Baumann J, Qiu Y, Matrosovich T, Klenk HD, Van Reeth K, Matrosovich M. 2015. Role of substitutions in the hemagglutinin in the emergence of the 1968 pandemic influenza virus. J Virol 89:12211-12216.
  • Bottcher-Friebertshauser E, Garten W, Matrosovich M, Klenk HD. 2014. The hemagglutinin: a determinant of pathogenicity. Curr Top Microbiol Immunol 385:3-34.
  • Linster M, Boheemen S, de Graaf M, Schrauwen EJA, Lexmond P, Manz B, Bestebroer TM, Baumann J, van Riel D, Rimmelzwaan GF, Osterhaus ADME, Matrosovich M, Fouchier RAM, Herfst S. 2014. Identification, characterization, and natural selection of mutations driving airborne transmission of A/H5N1 virus. Cell 157:329-339.
  • Hogner K, Wolff T, Pleschka S, Plog S, Gruber AD, Kalinke U, Walmrath HD, Bodner J, Gattenlohner S, Lewe-Schlosser P, Matrosovich M, Seeger W, Lohmeyer J, Herold S. 2013. Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia. Plos Pathog 9:e1003188.
  • Van Poucke S, Uhlendorff J, Wang ZF, Billiau V, Nicholls J, Matrosovich M, Van Reeth K. 2013. Effect of receptor specificity of A/Hong Kong/1/68 (H3N2) influenza virus variants on replication and transmission in pigs. Influenza and Other Respiratory Viruses 7:151-159.
  • Matrosovich M, Herrler G, Klenk HD. 2013. Sialic Acid Receptors of Viruses. Top Curr Chem 20:20.
  • Kolesnikova L, Heck S, Matrosovich T, Klenk HD, Becker S, Matrosovich M. 2013. Influenza virus budding from the tips of cellular microvilli in differentiated human airway epithelial cells. Journal of General Virology 94:971-976.
  • Klenk HD, Garten W, Matrosovich M. 2013. Pathogenesis, p 157-172. In Webster RG (ed), Textbook of Influenza, 2nd Edition. Wiley-Blackwell, Chichester, West Sussex, UK.
  • Crusat M, Liu JF, Palma AS, Childs RA, Liu Y, Wharton SA, Lin YP, Coombs PJ, Martin SR, Matrosovich M, Chen Z, Stevens DJ, Hien VM, Thanh TT, Nhu LNT, Nguyet LA, Ha DQ, van Doorn HR, Hien TT, Conradt HS, Kiso M, Gamblin SJ, Chai WG, Skehel JJ, Hay AJ, Farrar J, de Jong MD, Feizi T. 2013. Changes in the hemagglutinin of H5N1 viruses during human infection - Influence on receptor binding. Virology 447:326-337.
  • Corman VM, Eickmann M, Landt O, Bleicker T, Brunink S, Eschbach-Bludau M, Matrosovich M, Becker S, Drosten C. 2013. Specific detection by real-time reverse-transcription PCR assays of a novel avian influenza A(H7N9) strain associated with human spillover infections in China. Eurosurveillance 18:10-16.
  • Gambaryan, A. S., T. Y. Matrosovich, J. Philipp, V. J. Munster, R. A. Fouchier, G. Cattoli, I. Capua, S. L. Krauss, R. G. Webster, J. Banks, N. V. Bovin, H. D. Klenk, and M. N. Matrosovich. 2012. Receptor-binding profiles of H7 subtype influenza viruses in different host species. J.Virol. 86:4370-4379.
  • Liu, Y., R. A. Childs, T. Matrosovich, S. Wharton, A. S. Palma, W. Chai, R. Daniels, V. Gregory, J. Uhlendorff, M. Kiso, H. D. Klenk, A. Hay, T. Feizi, and M. Matrosovich. 2010. Altered receptor specificity and cell tropism of D222G hemagglutinin mutants isolated from fatal cases of pandemic A(H1N1) 2009 influenza virus. J.Virol. 84:12069-12074.
  • Childs, R. A., A. S. Palma, S. Wharton, T. Matrosovich, Y. Liu, W. Chai, M. A. Campanero-Rhodes, Y. Zhang, M. Eickmann, M. Kiso, A. Hay, M. Matrosovich, and T. Feizi. 2009. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat.Biotechnol. 27:797-799.
  • Ocana-Macchi, M., M. Bel, L. Guzylack-Piriou, N. Ruggli, M. Liniger, K. C. McCullough, Y. Sakoda, N. Isoda, M. Matrosovich, and A. Summerfield. 2009. Hemagglutinin-dependent tropism of H5N1 avian influenza virus for human endothelial cells. J.Virol. 83:12947-12955.
  • Matrosovich, M., T. Matrosovich, J. Uhlendorff, W. Garten, and H. D. Klenk. 2007. Avian-virus-like receptor specificity of the hemagglutinin impedes influenza virus replication in cultures of human airway epithelium. Virology. 361:384-390.
  • Gambaryan, A., S. Yamnikova, D. Lvov, A. Tuzikov, A. Chinarev, G. Pazynina, R. Webster, M. Matrosovich, and N. Bovin. 2005. Receptor specificity of influenza viruses from birds and mammals: new data on involvement of the inner fragments of the carbohydrate chain. Virology 334:276-283.
  • Matrosovich, M. N., T. Y. Matrosovich, T. Gray, N. A. Roberts, and H. D. Klenk. 2004. Human and avian influenza viruses target different cell types in cultures of human airway epithelium. Proc.Natl.Acad.Sci U.S.A 101:4620-4624.
  • Matrosovich, M., A. Tuzikov, N. Bovin, A. Gambaryan, A. Klimov, M. R. Castrucci, I. Donatelli, and Y. Kawaoka. 2000. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol. 74:8502-8512.
  • Jung S, von Thülen T, Laukemper V, Pigisch S, Hangel D, Wagner H, Kaufmann A, Bauer S. A single naturally occurring 2'-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand. PLoS One. 2015 Mar 18;10(3):e0120498. doi:10.1371/journal.pone.0120498. eCollection 2015.
  • Oldenburg M, Krüger A, Ferstl R, Kaufmann A, Nees G, Sigmund A, Bathke B, Lauterbach H, Suter M, Dreher S, Koedel U, Akira S, Kawai T, Buer J, Wagner H, Bauer S, Hochrein H, Kirschning CJ. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science. 2012 Aug 31;337(6098):1111-5. doi: 10.1126/science.1220363. Epub 2012 Jul 19.
  • Bauer, S., C. J. Kirschning, H. Hacker, V. Redecke, S. Hausmann, S. Akira, H. Wagner, and G. B. Lipford. 2001. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A 98:9237-42.
  • Hamm, S., A. Heit, M. Koffler, K. M. Huster, S. Akira, D. H. Busch, H. Wagner, and S. Bauer. 2007. Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo. Int Immunol 19:297-304.
  • Hamm, S., E. Latz, D. Hangel, T. Muller, P. Yu, D. Golenbock, T. Sparwasser, H. Wagner, and S. Bauer. 2010. Alternating 2'-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist. Immunobiology 215:559-69.
  • Heil, F., H. Hemmi, H. Hochrein, F. Ampenberger, C. Kirschning, S. Akira, G. Lipford, H. Wagner, and S. Bauer. 2004. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526-9.
  • Heil, F., P. Ahmad-Nejad, H. Hemmi, H. Hochrein, F. Ampenberger, T. Gellert, H. Dietrich, G. Lipford, K. Takeda, S. Akira, H. Wagner, and S. Bauer. 2003. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33:2987-97.
  • Jöckel, S., G. Nees, R. Sommer, Y. Zhao, D. Cherkasov, H. Hori, G. Ehm, M. Schnare, M. Nain, A. Kaufmann, and S. Bauer. 2012. The 2'-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition. J Exp Med 209:235-41.
  • Jurk, M., F. Heil, J. Vollmer, C. Schetter, A. M. Krieg, H. Wagner, G. Lipford, and S. Bauer. 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499.
  • Rutz, M., J. Metzger, T. Gellert, P. Luppa, G. B. Lipford, H. Wagner, and S. Bauer. 2004. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur J Immunol 34:2541-50.
Principal investigator:

Prof. Dr. Stephan Becker

Sprecher SFB 1021

Institut für Virologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 66253
E-Mail:
becker(at)staff.uni-marburg(dot)de


Research area: Molecular Virology

Marburg virus (MARV) causes lethal fever in humans and non-lethal infections in rodents. Sequential passaging of MARV in guinea pigs resulted in a guinea pig-adapted strain that contains 4 non-synonymous mutations and causes lethal disease. Cells of the mononuclear phagocyte system (MPS) were found to be the primary MARV targets in both lethal and non-lethal infection. The Becker group discovered that a single mutation in the viral matrix protein VP40 (D184N) improved the growth of recombinant MARV (rMARVVP40(D184N)) specifically in guinea pig cells. This phenotype correlated with a decreased ability of VP40D184N to suppress viral RNA synthesis in these cells. In primary MPS cells derived from a newly established ex vivo model, rMARVVP40(D184N) had a clear growth advantage over wild-type MARV. This correlated with the observation that rMARVVP40(D184N), in contrast to the non-lethal wild type virus, no longer induced cell death in the infected macrophages or in non-infected bystander cells. Other mutations in the guinea pig-adapted MARV were found to be located in the polymerase (L) coding sequence. One of the mutations located in the polymerase active site was shown to dramatically increase the viral transcription/replication activity.

Project-related publications of the investigator:
  • Dietzel E, Schudt G, Krähling V, Matrosovich M, Becker S. 2016. Functional characterization of adaptive mutations during the West African Ebola virus outbreak. J. Virol. 91:e01913-16.
  • Koehler A, Kolesnikova L, Becker S. 2016. An active site mutation increases the polymerase activity of the guinea pig-lethal Marburg virus. J Gen Virol. 97(10):2494-2500.
  • Koehler A, Kolesnikova L, Welzel U, Schudt G, Herwig A, Becker S. 2016. A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner. J Virol 90:1444-1454.
  • Wolff S, Groseth A, Meyer B, Jackson D, Strecker T, Kaufmann A, Becker S. 2016. The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells. J Gen Virol 97:855-866.
  • Dietzel E, Kolesnikova L, Sawatsky B, Heiner A, Weis M, Kobinger GP, Becker S, von Messling V, Maisner A. 2015. Nipah virus matrix protein influences fusogenicity and is essential for particle infectivity and stability. J Virol. 90(5):2514-22.
  • Schudt, G., O. Dolnik, L. Kolesnikova, N. Biedenkopf, A. Herwig and S. Becker. 2015. Transport of Ebolavirus Nucleocapsids Is Dependent on Actin Polymerization: Live-Cell Imaging Analysis of Ebolsvirus-Infected Cells. J. Infect Dis doi: 10.1093/infdis/jiv083
  • Kolesnikova, L., E. Mittler, G. Schudt, H. Shams-Eldin, and S. Becker. 2012. Phosphorylation of Marburg virus matrix protein VP40 triggers assembly of nucleocapsids with the viral envelope at the plasma membrane. Cell Microbiol 14:182-97
  • Mateo, M., C. Carbonnelle, O. Reynard, L. Kolesnikova, K. Nemirov, A. Page, V. A. Volchkova, and V. E. Volchkov. 2011. VP24 is a molecular determinant of Ebola virus virulence in guinea pigs. J Infect Dis 204 Suppl 3:S1011-20.
  • Welsch, S., L. Kolesnikova, V. Krahling, J. D. Riches, S. Becker, and J. A. Briggs. 2010. Electron tomography reveals the steps in filovirus budding. PLoS Pathog 6:e1000875.
  • Krahling, V., O. Dolnik, L. Kolesnikova, J. Schmidt-Chanasit, I. Jordan, V. Sandig, S. Gunther, and S. Becker. 2010. Establishment of fruit bat cells (Rousettus aegyptiacus) as a model system for the investigation of filoviral infection. PLoS Negl Trop Dis 4:e802.
  • Dolnik, O., L. Kolesnikova, and S. Becker. 2008. Filoviruses: Interactions with the host cell. Cell Mol Life Sci 65:756-76.
  • Kolesnikova, L., A. B. Bohil, R. E. Cheney, and S. Becker. 2007. Budding of Marburgvirus is associated with filopodia. Cell Microbiol 9:939-51.
  • Kolesnikova, L., B. Berghofer, S. Bamberg, and S. Becker. 2004. Multivesicular bodies as a platform for formation of the Marburg virus envelope. J Virol 78:12277-87.
  • Kolesnikova, L., S. Bamberg, B. Berghofer, and S. Becker. 2004. The matrix protein of Marburg virus is transported to the plasma membrane along cellular membranes: exploiting the retrograde late endosomal pathway. J Virol 78:2382-93.
  • Ryabchikova, E. I., L.  Kolesnikova, and S. V. Luchko. 1999. An analysis of features of pathogenesis in two animal models of Ebola virus infection. J Infect Dis 179 Suppl 1:S199-202.
  • Mühlberger, E., B. Lotfering, H.-D. Klenk, and S. Becker. 1998. Three of the four nucleocapsid proteins of Marburg virus, NP, VP35, and L, are sufficient to mediate replication and transcription of Marburg virus-specific monocistronic minigenomes. J Virol 72:8756-64.
  • Ryabchikova, E., L. Kolesnikova, M. Smolina, V. Tkachev, L. Pereboeva, S. Baranova, A. Grazhdantseva, and Y. Rassadkin. 1996. Ebola virus infection in guinea pigs: presumable role of granulomatous inflammation in pathogenesis. Arch Virol 141:909-21.
  • Ryabchikova, E., L. Strelets, L. Kolesnikova, O. Pyankov, and A. Sergeev. 1996. Respiratory Marburg virus infection in guinea pigs. Arch Virol 141:2177-90.
Principal investigator:

Prof. Dr. Andrea Maisner

Institut für Virologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 65360
E-Mail: maisner(at)staff.uni-marburg(dot)de


Research area: Molecular Virology

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 E, Sauerhering L, & Maisner A (2019). Cytokine induction in Nipah virus infected primary human and porcine bronchial epithelial cells. J Infect Dis; doi: 10.1093/infdis/jiz455. [Epub ahead of print]
  • 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. 2019 Apr 29;15(4):e1007733.
  • 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.
  • Bender RR, Muth A, Schneider IC, Friedel T, Hartmann, JA, Maisner A, & Buchholz CJ (2016). Receptor-targeted Nipah virus glycoproteins improve cell-type selective gene delivery and reveal a preference for membrane-proximal cell attachment. PLoS Path 12(6):e1005641.
  • Dietzel E, Kolesnikova L, Sawatsky B, Heiner A, Weis M, Kobinger GP, Becker S, von Messling V, & Maisner A (2015). Nipah virus matrix protein influences fusogenicity and is essential for particle infectivity and stability. J. Virol. 90: 2514-2522.
  • Freitag TC, & Maisner A. (2015). Early activation of primary brain microvascular endothelial cells by Nipah virus glycoprotein containing particles. J. Virol. 90: 2706-2709.
  • Lamp B, Dietzel E, Kolesnikova L, Sauerhering L, Erbar S, Weingartl H, & Maisner A (2013). Nipah virus entry and egress from polarized epithelial cells. J. Virol. 87, 3143-3154.
  • Diederich S, Sauerhering L, Weis M, Altmeppen H, Schaschke N, Reinheckel T, Erbar S, & Maisner A (2012). Activation of the Nipah virus fusion protein in MDCK cells is mediated by cathepsin B within the endosome-recycling compartment. J. Virol. 86, 3736-3745.
  • Weise C, Erbar S, Lamp B, Vogt C, Diederich S, & Maisner A (2010). Tyrosine residues in the cytoplasmic domains affect sorting and fusion activity of the Nipah virus glycoproteins in polarized epithelial cells. J. Virol. 84, 7634–7641.
  • Diederich S, Moll M, Klenk HD, & Maisner A (2005). The Nipah virus fusion protein is cleaved within the endosomal compartment. J. Biol. Chem. 280:29899-903.
Principal investigator:

Dr. Thomas Strecker

Institut für Virologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 65182
E-Mail:
strecker(at)staff.uni-marburg(dot)de


Research area: Molecular Virology

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:
  • Olayemi A, Adesina AS, Strecker T, Magassouba N, Fichet-Calvet E., 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). 2020 Feb 7;9(2). pii: E26. doi: 10.3390/biology9020026.
  • Watanabe Y, Raghwani J, Allen JD, Seabright GE, Li S, Moser F, Huiskonen JT, Strecker T, Bowden TA, Crispin M. Structure of the Lassa virus glycan shield provides a model for immunological resistance. Proc Natl Acad Sci U S A. 2018 Jun 25. pii: 201803990.
  • Whitmer SLM, Strecker T, Cadar D, Dienes HP, Faber K, Patel K, Brown SM, Davis WG, Klena JD, Rollin PE et al., New Lineage of Lassa Virus, Togo, 2016. Emerg Infect Dis. 2018 Mar;24(3):599-602.
  • Sauerhering L, Müller H, Behner L, Elvert M, Fehling SK, Strecker T, Maisner A. Variability of interferon-λ induction and antiviral activity in Nipah virus infected differentiated human bronchial epithelial cells of two human donors. J Gen Virol. 2017 Oct;98(10):2447-2453.
  • Huber M, Suprunenko T, Ashhurst T, Marbach F, Raifer H, Wolff S, Strecker T et al., IRF9 prevents CD8+ T cell exhaustion in an extrinsic manner during acute LCMV infection. J Virol. 2017 Sep 6. pii: JVI.01219-17.
  • Wolff S, Schultze T, Fehling SK, Mengel JP, Kann G, Wolf T, Eickmann M, Becker S, Hain T, Strecker T. Genome Sequence of Lassa Virus Isolated from the First Domestically Acquired Case in Germany. Genome Announc. 2016 Sep 22;4(5).
  • S. Li, Z. Sun, R. Pryce, M.-L. Parsy, S. K. Fehling, K. Schlie, A. Siebert, W. Garten, T. A. Bowden, T. Strecker, J. T. Huiskonen. Acidic pH-induced Conformations and LAMP1 binding of the Lassa Virus Glycoprotein Spike. PLoS Pathog (2016)
  • S. Wolff, A. Groseth, B. Meyer, D. Jackson, T. Strecker, A. Kaufmann, S. Becker, The New World Arenavirus Tacaribe induces caspase-dependent apoptosis in infected cells. J Gen Virol 10.1099/jgv.0.000403 (2016).
  • S. K. Fehling, T. Noda, A. Maisner, B. Lamp, K. K. Conzelmann, Y. Kawaoka, H. D. Klenk, W. Garten, T. Strecker, The microtubule motor protein KIF13A is involved in intracellular trafficking of the Lassa virus matrix protein Z. Cell Microbiol 15, 315-334 (2013).
  • S. K. Fehling, F. Lennartz, T. Strecker, Multifunctional nature of the arenavirus RING finger protein Z. Viruses 4, 2973-3011 (2012).
Principal investigator:

Prof. Dr. Friedemann Weber

Institut für Virologie
FB Veterinärmedizin
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 38350
E-mail: friedemann.weber(at)vetmed.uni-giessen(dot)de


Research area: Molecular Virology

A key virulence factor of bunyaviruses is the non-structural protein NSs, an inhibitor of the antiviral type I interferon (IFN-alpha/beta) system. Previously, the Weber group demonstrated that NSs of Rift valley fever virus (RVFV) blocks the induction of IFN on the transcriptional level, and degrades the antiviral IFN effector PKR via the proteasome. It remained however unclear how IFN induction and PKR activation occur at all, and how NSs counteracts these processes. In the first CRC 1021 funding period, the Weber group identified two regulatory dsRNA structures, namely the “panhandle” and the intergenic region (IGR) of the viral genome, as activators of RIG-I (and hence IFN induction) and PKR, respectively. Moreover, they discovered that RVFV NSs recruits the cellular F-box type ubiquitin ligase subunits FBXO3 and FBXW11/beta-TRCP1 to destroy the general host cell transcription factor TFIIB-p62 (involved in IFN gene induction) and PKR, respectively. In addition, the Weber group observed that RVFV NSs impairs the nuclear export of host mRNAs and that NSs from other bunyaviruses use different mechanisms to block IFN response and PKR activation in infected cells.

Project-related publications of the investigator:
  • Schoen, A., S. Lau, P. Verbruggen, F. Weber (2020): Elongin C contributes to RNA polymerase II degradation by the interferon antagonist NSs of La Crosse orthobunyavirus. J. Virol. In press
  • Barr, J.D., F. 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*, F. Weber* (2019): Virus- and interferon alpha-induced transcriptomes of cells from the microbat Myotis daubentonii. iScience, 19, 647–661
  • Lau, S., F. 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., F. 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, F. 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, F. 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, F. 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., F. Weber, D. Frishman (2017): Conserved RNA structures in the intergenic regions of ambisense viruses. Scientific Reports, Article number: 16625
  • Ferron, F, 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
Principal investigator:

Prof. Dr. Eva Böttcher-Friebertshäuser

Institut für Virologie
Philipps-Universität Marburg
Hans-Meerwein-Str. 2
35043 Marburg

Phone: 06421-28 66019
E-mail: friebertshaeuser(at)staff.uni-marburg(dot)de


Research area: Molecular Virology

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:
  • Limburg, H., Harbig, A., Bestle, D., Stein, D. A., Moulton, H. M., Jaeger, J., Janga, H., Hardes, K., Koepke, J., Schulte, L., Koczulla, A. R., Schmeck, B., Klenk, H.-D., Böttcher-Friebertshäuser, E.  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. 2019; 93: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. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol. 2014;88:4744-51.
  • Peitsch C, Klenk HD, Garten W, Böttcher-Friebertshäuser E. Activation of Influenza A Viruses by Host Proteases from Swine Airway Epithelium. J Virol. 2014;88:282-91
  • 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. Matriptase, HAT and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol. 2013;87:1811-20.
  • Böttcher-Friebertshäuser E, Lu Y, Meyer D, Sielaff F, Steinmetzer T, Klenk HD, Garten W. Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections. Vaccine. 2012;30:7374-80.
  • Böttcher-Friebertshäuser E, Stein DA, Klenk HD, Garten W. 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. 2011;85:1554-62.
  • Böttcher-Friebertshäuser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J, Steinmetzer T, Klenk HD, Garten W. Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol. 2010;84:5605-14.
  • Okumura Y, Takahashi E, Yano M, Ohuchi M, Daidoji T, Nakaya T, Böttcher E, Garten W, Klenk HD, Kido H. Novel type II transmembrane serine proteases, MSPL and TMPRSS13, proteolytically activate membrane fusion activity of the hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication. J Virol. 2010;84:5089-96.
  • Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol. 2006;80:9896-8.
Principal investigator:

Prof. Dr. Dieter Glebe

Institut für Medizinische Virologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 41246
E-Mail:
dieter.glebe(at)viro.med.uni-giessen(dot)de


Principal investigator:

Prof. Dr. Joachim Geyer

Institut für Pharmakologie und Toxikologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 38404
E-Mail:
joachim.m.geyer(at)vetmed.uni-giessen(dot)de


Research area: Molecular and Medical Virology/Molecular Pharmacology

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:
  • 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*. Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses. Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):17007-17012. doi: 10.1073/pnas.1908072116. (*shared senior authors).
  • Noppes S, Müller SF, Bennien J, Holtemeyer M, Palatini M, Leidolf R, Alber J, Geyer J. Homo- And Heterodimerization Is a Common Feature of the Solute Carrier Family SLC10 Members. Biol Chem. 2019 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. Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling. Int J Mol Sci. 2019 Mar 15;20(6).
  • Müller SF, König A, Döring B, Glebe DGeyer J. 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 2018 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*. A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses. J Hepatol. 2018 Jun;68(6):1114-1122., (*shared senior authors).
  • König A, Döring B, Mohr C, Geipel A, Geyer JGlebe D. Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes. J. Hepatol. 2014 October 61,(4) 867-875.
  • Drexler JF, Geipel A, König A, Corman VM, van Riel D, Leijten LM, Bremer CM, Rasche A, Cottontail VM, Maganga GD, Schlegel M, Müller MA, Adam A, Klose SM, Borges Carneiro AJ, Stöcker A, Franke CR, Gloza-Rausch F, Geyer J, Annan A, Adu-Sarkodie Y, Oppong S, Binger T, Vallo P, Tschapka M, Ulrich RG, Gerlich WH, Leroy E, Kuiken T, Glebe D*, Drosten C*. Bats carry pathogenic hepadnaviruses antigenically related to hepatitis B virus and capable of infecting human hepatocytes. Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16151-16156. (*shared senior authors).
  • Döring B, Lütteke T, Geyer J, Petzinger E. The SLC10 Carrier Family: Transport Functions and Molecular Structure 2012. In: M.O. Bevensee (Ed.), Co Transport Systems (pp. 105-168). Elsevier Inc. ISBN: 9780123943163.
  • Bijsmans ITGW, Bouwmeester RAM, Geyer J, Faber KN, van de Graaf SFJ. Homo- and heterodimeric architecture of the human liver Na+-dependent taurocholate cotransporting protein NTCP. Biochem J 2011;441(3):1007-1015.
  • Bremer CM, Sominskaya I, Skrastina D, Pumpens P, Abd El Wahed A, Beutling U, Frank R, Fritz HJ, Hunsmann G, Gerlich WH, Glebe D. N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus. J. Hepatol. 2011 Jul;55(1):29-37
Principal investigator:

Prof. Dr. Veronika von Messling

Paul-Ehrlich-Institut
Paul-Ehrlich-Str. 51
63225 Langen

Phone: 06103-777 400
E-mail: veronika.vonmessling(at)pei(dot)de


Research area: Molecular Virology

The genomes of RNA viruses exist as quasispecies, due to the lack of proof-reading ability of their RNA-dependent RNA polymerase. The next-generation sequencing technology has provided new insights into the contribution of this genetic plasticity to adaptation and emergence of resistant variants in vitro, but the role of this plasticity in pathogenesis remains largely unknown. Canine distemper virus (CDV), a non-segmented negative-stranded RNA virus of the Morbillivirus genus in the Paramyxoviridae family, causes a lethal disease in ferrets. The von Messling group has shown that the virus initially amplifies in the immune system and that the subsequent spread to epithelial tissues coincides with the onset of clinical signs and transmission to a new host. Since the infection leads to extensive virus amplification in the respective target tissues, this system is ideally suited to directly characterize the viral genetic plasticity in vivo. First preliminary analyses of the sequence diversity in immune and epithelial tissues revealed distinct differences between virus inoculum and populations found at the end stages of infection. Based on these observations, this project will test the hypothesis that quasispecies contribute to virulence through modulation of dissemination and replication efficiency. It will provide new insights into the contribution of genetic plasticity to Morbillivirus biology, and pinpoint genome regions or motifs that are critical for virulence. The mechanistic concepts and experimental approaches developed in this system may also be applicable to other negative-stranded RNA viruses.

Project-related publications of the investigator:
  • Höper D, Freuling CM, Müller T, Hanke D, von Messling V, Duchow K, Beer M, Mettenleiter TC. High definition viral vaccine strain identity and stability testing using full-genome population data--The next generation of vaccine quality control. Vaccine 2015; 33: 5829-37.
  • Krumm SA, Yan D, Hovingh E, Evers TJ, Enkirch T, Reddy GP, Sun A, Saindane MT,Arrendale RF, Painter G, Liotta DC, Natchus MG, von Messling V, Plemper RK. An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci. Transl. Med. 2014; 6: 232.
  • Svitek N, Gerhauser I, Goncalves C, Grabski E, Döring M, Kalinke U, Anderson DE, Cattaneo R, von Messling V. Morbillivirus control of the interferon response:relevance of STAT2 and mda5 but not STAT1 for canine distemper virus virulence in ferrets. J. Virol. 2014; 88: 2941-2950.
  • Frenzke M, Sawatsky B, Wong XX, Depeut S, Mateo M, Cattaneo R, von Messling V. Nectin-4-dependent measles virus spread to the cynomolgus monkey tracheal epithelium: role of infecting immune cells infiltrating the lamina propria. 2013; J. Virol. 87: 2526-2534.
  • Mühlebach MD, Mateo M, Sinn PL, Prüfer S, Uhlig KM, Leonard VHJ, Navaratnarajah CK, Frenzke M, Wong XX, Sawatsky B, Ramachandran S, McCray PB, Cichutek K, von Messling V, Lopez M, Cattaneo R. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 2011; 480: 530-533.
  • Pillet S and von Messling V. Canine distemper virus selectively inhibits apoptosis progression in infected immune cells. J. Virol. 2009; 83: 6279-6287.
  • Anderson D and von Messling V. The region between the canine distemper virus M and F genes modulates virulence by controlling fusion protein expression. J. Virol. 2008; 82: 10510-10518.
  • Bonami F, Rudd PA, and von Messling V. Disease duration determines canine distemper virus neurovirulence. J. Virol. 2007; 81: 12066-12070.
  • Rudd PA, Cattaneo R, and von Messling V. Canine distemper virus uses both the anterograde and the hematogenous pathway for neuroinvasion. J. Virol. 2006; 80: 9361-9370.
  • von Messling V, Milosevic D, Cattaneo R. Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system. Proc. Natl. Acad. Sci. 2004; 101: 14216-14221.