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Research Group PD Dr. rer. nat. Barbara Adler

 

Biology of Cytomegaloviruses

 

Areas of investigation

Human cytomegalovirus can cause life-threatening infections in immunocompromised hosts and is the leading cause of birth defects among congenitally transmitted viral infections. Currently, no approved vaccines exist which can protect from HCMV infection. This is mainly due to an elaborate viral machinery that in many ways interferes with the innate and adaptive antiviral immune responses of humans. In the past, elucidating this viral interference has strongly contributed to understanding human and mouse immune defense pathways. The capacity to shape the immune response of their hosts makes cytomegaloviruses highly interesting vectors for vaccination or tumor therapy. Recent research indicates that virus mutants lacking specific viral immune regulatory genes differentially protect from e.g. HIV or Mycobacterium tuberculosis. Future prospects are custom-made CMV vectors for vaccination against specific infectious agents or treatment of diverse types of cancer. We are specifically interested in CMV envelope glycoprotein complexes, which simultaneously promote virus entry and shape antiviral immune responses.

BAC technology

One central tool to study the role of viral proteins are cytomegalovirus genomes cloned as bacterial artificial chromosomes (BAC). Cloning herpesvirus genomes as BAC involves insertion of huge (200.000 bp) long DNA genomes in bacterial vectors, subsequent mutagenesis in E.coli and reconstitution of these modified genomes by transfection of host cells. Using BAC technology, we can mutate, delete, or overexpress viral proteins or insert reporter genes like GFP or luciferase.

CMV gH/gL envelope glycoprotein complexes

We are interested in the roles of envelope glycoprotein complexes of human cytomegalovirus (HCMV) and of murine cytomegalovirus (MCMV), which serves as an animal model. The envelope glycoproteins in focus of our research are gH/gL glycoprotein complexes, which determine the cell tropism and which are important targets of virus-neutralizing antibodies. Cytomegaloviruses express different gH/gL complexes, which recognize different receptors. The virus producing cells determine which gH/gL complexes are included in the virions and thus cell-type dependently contribute to virus navigation in the infected host. Very specific for CMV, one of the gH/gL complexes contains a viral chemokine, which in addition to promoting receptor recognition also shapes the antiviral immune response. We have analyzed many mutants of gH/gL complexes with the aim to identify their cellular receptors and to study their roles in virus dissemination and in shaping the antiviral adaptive and innate immune responses.

CMV vectors

Cytomegaloviruses are attractive vectors for expressing foreign antigens in their hosts and eliciting strong and long lasting T cell responses. Two features make them exceptional: (i) Viral inhibitors of CD8 T cell responses allow superinfection with the same vector and thus repeated vaccinations and (ii) Modulation of the viral equipment of immune modulatory genes enables the construction of vectors eliciting highly diverse patterns of immune responses. Our current focus are vectors expressing and lacking viral chemokines and the analysis of their potential as vaccine vectors.

Current Group Members

Barbara Adler, PhD, PD, group leader
Email: adler_b(at)mvp.uni-muenchen.de

Marwa Eletreby, PhD student
Email: eletreby@mvp.uni-muenchen.de
Phone +49 89-2180-72889

Josipa Jerak, Master of Science
Email: jerak(at)mvp.uni-muenchen.de
Phone +49 89-2180-72889

Former lab members

Regina Bichler (Bachelor student)
Ilija Brizic (visiting PhD student)
Heike Hofmann (Technician)
Laura Jochem (Bachelor student)
Marisa Kurz (Bachelor Student)
Adrian Prager (Technician)
Sabrina Schuller (Bachelor student)
Laura Scrivano (PhD student and postdoc)
Jasmina Esterlechner (Master student)
Yiquan Wu (PhD student)
Thomas Deiler (bachelor student)

Publications

Recent key publications

Wu, Y., Prager, A., Boos, S., Resch, M., Brizic, I., Mach, M., Wildner, S., Scrivano, L. and Adler, B. (2017) Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry. PLoS Pathog 13 (4): e1006281

Hagen C., Dent K.C., Zeev-Ben-Mordehai T., Grange M., Bosse J.B., Whittle C., Klupp B.G., Siebert C.A., Vasishtan D., Bäuerlein F.J., Cheleski J., Werner S., Guttmann P., Rehbein S., Henzler K., Demmerle J., Adler B., Koszinowski U., Schermelleh L., Schneider G., Enquist L.W., Plitzko J.M., Mettenleiter T.C., Grünewald K. (2015) Structural Basis of Vesicle Formation at the Inner Nuclear Membrane. Cell 163(7),1692-701.

Lemmermann, N.A., Krmpotic, A., Podlech, J., Brizic, I., Prager ,A., Adler, H., Karbach, A., Wu, Y., Jonjic, S., Reddehase, M.J., and Adler, B. (2015) Non-redundant and redundant roles of Cytomegalovirus gH/gL complexes in host organ entry and intra-tissue spread. PLoS Pathog 11(2):e1004640

Wagner, F., Brizic, I., Prager, A., Trsan, T., Arapovic, M., Lemmermann, N.A.W., Podlech, J., Reddehase, M.J., Lemnitzer, F., Bosse, J-B., Gimpfl, M., Marcinowski, L., MacDonald, M., Adler, H., Koszinowski, U.H. and Adler, B. (2013) The Viral Chemokine MCK-2 of Murine Cytomegalovirus Promotes Infection as Part of a gH/gL/MCK-2 Complex. PLoS Pathog 9(7): e1003493

Jordan, S., Krause, J., Prager, A., Mitrovic, M., Jonjic, S., Koszinoswki, U.H., and Adler, B. (2011) Virus progeny of Murine Cytomegalovirus Bacterial Artificial Chromosome pSM3fr show reduced growth in Salivary Glands due to fixed mutation of MCK-2. J Virol 85, 10346-10353

Scrivano, L., Sinzger C., Nitschko, H., Koszinowski, U.H. and Adler, B. (2011) HCMV spread and cell tropism are determined by distinct virus populations. PLoS Pathog 7(1): e10011256

Contact

PD Dr. Barbara Adler
Max von Pettenkofer Institute, Virology
National Reference Center for Retroviruses
Faculty of Medicine
LMU München
Feodor-Lynen-Straße 25
81377 Munich, Germany
Tel.: 089-2180-76863 / Labor -76850
Email: adler_b(at)mvp.uni-muenchen.de