AG Messerle

Research summary

Cytomegalovirus (CMV) research group

The lab focuses on the regulation of gene expression and RNA biology. In terms of viruses we dissect the regulation of herpesviral RNA expression. On the cellular side we are interested in non-coding mutations causing various human diseases. Both areas follow our central idea: A deeper knowledge of both viral gene expression and the pathomechanisms of non-coding mutations will advance our understanding of cellular processes.

Human cytomegalovirus (HCMV) is a widespread pathogen, with 50-80% of the population being infected. Primary infection in healthy persons is usually asymptomatic, but life-threaten­ing disease can occur in immunocompromised patients, especially in transplant recipients or AIDS patients. HCMV infection is also the most frequent viral infection during pregnancy, often leading to malformation of the fetus, with a typically manifestation being deafness.

In order to make cytomegalovirus functions amenable to efficient genetic analysis, many years ago we cloned the genomes of mouse and human cytomegalovirus as bacterial artificial chromosomes (BAC) in E.coli (Messerle et al., 1997; Borst et al., 1999). This allows us to manipulate the viral genomes by the powerful techniques of bacterial genetics and to generate viral mutants upon transfection of permissive eukaryotic cells with mutated BACs. By analyzing the phenotypes of the mutant viruses viral functions can be assigned to specific genes.

During the long co-evolution with their hosts, CMVs have developed various strate­gies to modulate important pathways of infected cells. Many viral functions enabling the viruses to exploit the host cells for their own ends are poorly understood or remain elusive. We are interested in the interaction of cytomegaloviruses with their host cells and the modulation of the immune response, particularly during persisting infection. Based on the knowledge of virus-cell interactions we test vaccination concepts against HCMV using suitable mutants. Not least, we investigate how infected cells support the assembly and the maturation of new CMV particles and aim at the development of antivirals disrupting the viral life cycle.

Publications in peer-reviewed journals, Reviews, Book chapters, Comments etc.

selected publications:

1. Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells.
Nat Immunol. 2018, 19:453-463.

2. Kutle I, Sengstake S, Templin C, Glaß M, Kubsch T, Keyser KA, Binz A, Bauerfeind R, Sodeik B, Čičin-Šain L, Dezeljin M, Messerle M. The M25 gene products are critical for the cytopathic effect of mouse cytomegalovirus.
Scientific Reports 2017, 7:e15588.

3. Neuber S, Wagner K, Goldner T, Lischka P, Steinbrueck L, Messerle M, Borst EM. Mutual interplay between the human cytomegalovirus terminase subunits pUL51, pUL56, and pUL89 promotes terminase complex formation.
J Virol. 2017, 9: e02384-16.

4. Borst EM, Bauerfeind R, Binz A, Stephan TM, Neuber S, Wagner K, Steinbrück L, Sodeik B, Lenac Roviš T, Jonjić S, Messerle M. The essential human cytomegalovirus proteins pUL77 and pUL93 are structural components necessary for viral genome encapsidation
J Virol. 2016, 90:5860-75.

5. Thiel N, Keyser KA, Lemmermann NA, Oduro JD, Wagner K, Elsner C, Halenius A, Lenac Roviš T, Brinkmann MM, Jonjić S, Cicin-Sain L, Messerle M. The mouse cytomegalovirus gene m42 targets surface expression of the protein tyrosine phosphatase CD45 in infected macrophages.
PLoS Pathog. 2016, 12:e1006057.

6. Tomić A, Varanasi PR, Golemac M, Malić S, Riese P, Borst EM, Mischak-Weissinger E, Guzmán CA, Krmpotić A, Jonjić S, Messerle M. Activation of innate and adaptive immunity by a recombinant human cytomegalovirus strain expressing an NKG2D ligand.
PLoS Pathog. 2016, 12:e1006015.

7. Halle S, Keyser KA, Stahl FR, Busche A, Marquardt A, Zheng X, Galla M, Heissmeyer V, Heller K, Boelter J, Wagner K, Bischoff Y, Martens R, Braun A, Werth K, Uvarovskii A, Kempf H, Meyer-Hermann M, Arens R, Kremer M, Sutter G, Messerle M, Förster R. In vivo killing capacity of cytotoxic T cells is limited and involves dynamic interactions and T cell cooperativity.
Immunity 2016, 44:233-45.

8. Borst EM, Kleine-Albers J, Gabaev I, Babic M, Wagner K, Binz A, Degenhardt I, Kalesse M, Jonjic S, Bauerfeind R, Messerle M. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89.
J Virol. 2013, 87:1720-32.

9. Busche A, Jirmo AC, Welten SP, Zischke J, Noack J, Constabel H, Gatzke AK, Keyser KA, Arens R, Behrens GM, Messerle M. Priming of CD8+ T cells against cytomegalovirus-encoded antigens is dominated by cross-presentation.
J Immunol. 2013, 190:2767-77.

10. Trsan T, Busche A, Abram M, Wensveen FM, Lemmermann NA, Arapovic M, Babic M, Tomic A, Golemac M, Brinkmann MM, Jäger W, Oxenius A, Polic B, Krmpotic A, Messerle M, Jonjic S. Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ.
Proc Natl Acad Sci USA 2013, 110:16550-5.

11. Slavuljica I, Busche A, Babić M, Mitrović M, Gašparović I, Cekinović D, Markova Car E, Pernjak Pugel E, Ciković A, Lisnić VJ, Britt WJ, Koszinowski U, Messerle M, Krmpotić A, Jonjić S. Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties.
J Clin Invest. 2010, 120:4532-45.

12. Glaß, M., Busche, A., Wagner, K., Messerle, M., Borst, E.M. Conditional and reversible disruption of essential herpesvirus proteins.
Nature Methods 2009, 6:577-9.

13. Borst, E.M., Hahn, G., Koszinowski, U.H., Messerle, M. Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants.
J Virol. 1999, 73:8320-9.

14. Messerle, M., Crnkovic, I., Ziegler, H., Hammerschmidt, W., Koszinowski, U.H. Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome.
Proc Natl Acad Sci USA 1997, 94:14759-63.

Complete Publication list:
https://www.ncbi.nlm.nih.gov/pubmed/?term=messerle-m