Virology


Research Group PD Dr. rer. nat. Barbara Adler

Human cytomegalovirus (HCMV) infections are a major cause of morbidity and mortality in immunocompromised humans like transplant patients or the unborn or prematurely born child. Currently available anti-HCMV treatments are very costly, associated with severe side effects, and the development of drug resistance. A licensed vaccine to protect from HCMV infection does not exist. Common targets for antiviral therapy are for example envelope glycoproteins, which promote virus entry. Our research focus is CMV gHgL glycoprotein complexes. We study mechanisms of gHgL glycoprotein-dependent entry, the role of these complexes in virus infections, their potential as vaccine antigens, and when using CMV as a vaccine vector, their role in shaping the vaccine-induced immune response.

The Research Group

Chair

PD Dr. rer. nat. Barbara Adler

Barbara Adler, PhD, is principal investigator at the Max von Pettenkofer Institute, Virology, at LMUMunich. She studied Biology in Freiburg (Germany) and Edinburgh (UK), and completed her doctoral studies at the Albert-Ludwigs-University in Freiburg. Following postdoctoral periods with a focus on virology and immunology at the University of Bern (Switzerland), the Dana Farber Cancer Institute in Boston (USA), and the Helmholtz Center Munich, she became principal investigator at the Max von Pettenkofer Institute. She completed her “Habilitation” in Virology at the Medical Faculty of the LMU Munich.

Group Members

Current Group Members

Barbara Adler, PhD, principal investigator
E-Mail: adler_b@mvp.lmu.de
Phone: +49 89 2180-76863

Katharina Jäger, PhD student
E-Mail: k.jaeger@mvp.lmu.de
Phone: +49 89 2180-76850

Lucie Kubic, technician
E-Mail: kubic@mvp.lmu.de
Phone: +49 89 2180-76855

Lena Thiessen, PhD student
E-Mail: thiessen@mvp.lmu.de
Phone: +49 89 2180-76850

Elena Savio, Master student
E-Mail: savio@mvp.lmu.de
Phone: +49 89 2180-76850

Former Group Members

  • Evelyn Schaad (PhD student)
  • Barbara Bayer (technician)
  • Laura Scrivano (PhD student, postdoctoral fellow)
  • Heike Hofmann (technician)
  • Laura Jochem (Bachelor student)
  • Sabrina Schuller (Bachelor student)
  • Jasmina Seoul-Esterlechner (Master student)
  • Adrian Prager (technician)
  • Marisa Kurz (Bachelor student)
  • Ilija Brizic (visiting scientist)
  • Yiquan Wu (PhD student)
  • Thomas Deiler (Master student)
  • Regina Bichler (Bachelor student)
  • Christine Weiss (Bachelor student)
  • Simone Boos (technician)
  • Josipa Jerak (visiting scientist)
  • Krizan Jurinovic (Bachelor student)
  • Ursula Rambold (Master student)
  • Tina Jenus (visiting scientist)
  • Irene Görzer (visiting scientist)
  • Lorenzo Apolloni (Master student)
  • Max Holzwarth (Master student)
  • Roberto Garuti (Master student)
  • Marwa Eletreby (PhD student)

Research

Cytomegaloviruses and the immune system

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.

BAC-mutagenesis

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), the latter serving 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 cellular 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 a set of mutants of gH/gL complexes with the aim to identify their specific 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.

Publications

Top 10 Publications

Eletreby M, Thiessen L, Prager A, Brizic I, Materljan J, Kubic L, Jäger K, Jurinović K, Jerak J, Krey K, Adler B. Dissecting the cytomegalovirus CC chemokine: Chemokine activity and gHgLchemokine-dependent cell tropism are independent players in CMV infection. PLoS Pathog. 2023 Dec 8;19(12):e1011793. doi: 10.1371/journal.ppat.1011793. PMID: 38064525; PMCID: PMC10732436.
Rožmanić C, Lisnić B, Pribanić Matešić M, Mihalić A, Hiršl L, Park E, Lesac Brizić A, Indenbirken D, Viduka I, Šantić M, Adler B, Yokoyama WM, Krmpotić A, Juranić Lisnić V, Jonjić S, Brizić I. Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells. Nat Commun. 2023 Oct 12;14(1):6412. doi: 10.1038/s41467-023-42182-w. PMID: 37828009; PMCID: PMC10570381.
Adler, B, Adler, H. Type I interferon signaling and macrophages: a double-edged sword? Cell Mol Immunol 19(9):967-968. (2022). https://doi.org/10.1038/s41423-020-00609-0
Adler, B, Sattler, C, Adler, H. Herpesviruses and their Host Cells: a Successful Liaison.Trends in Microbiology 25 (3): 229-241 (2017). https://doi.org/10.1016/j.tim.2016.11.009
Wu, Y, Prager, A, Boos, S, Resch, M, Brizic, I, Mach, M, Wildner, S, Scrivano, L, and Adler, B. Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry. PLoS Pathogens 13 (4): e1006281 (2017). https://doi.org/10.1371/ppat.1006281
Hagen, C, Dent, KC, Zeev-Ben-Mordehai, T, Grange, M, Bosse, JB, Whittle, C, Klupp, BG, Siebert, CA, Vasishtan, D, Bäuerlein, FJ, Cheleski, J, Werner, S, Guttmann, P, Rehbein, S, Henzler, K, Demmerle, J, Adler, B, Koszinowski, U, Schermelleh, L, Schneider, G, Enquist, LW, Plitzko, JM, Mettenleiter, TC, Grünewald, K. Structural Basis of Vesicle Formation at the Inner Nuclear Membrane. Cell 163:1692-701 (2015). https://doi.org/10.1016/j.cell.2015.11.029
Lemmermann NA, Krmpotic A, Podlech J, Brizic I, Prager A, Adler H, Karbach A, Wu Y, Jonjic S, Reddehase MJ, Adler B. Non-redundant and redundant roles of cytomegalovirus gH/gL complexes in host organ entry and intra-tissue spread. PLoS Pathogens 11(2):e1004640 (2015). https://doi.org/10.1371/ppat.1004640
Wagner, F, Brizic, I, Prager, A, Trsan, T, Arapovic, M, Lemmermann, NAW, Podlech, J, Reddehase, MJ, Lemnitzer, F, Bosse, J-B, Gimpfl, M, Marcinowski, L, MacDonald, M, Adler, H, Koszinowski, UH, Adler, B. The Viral Chemokine MCK-2 of Murine Cytomegalovirus Promotes Infection as Part of a gH/gL/MCK-2 Complex. PLoS Pathog. 9(7): e1003493 (2013). https://doi.org/10.1371/ppat.1003493
Jordan, S, Krause, J, Prager, A, Mitrovic, M, Jonjic, S, Koszinoswki, UH, Adler, B. Virus progeny of Murine Cytomegalovirus Bacterial Artificial Chromosome pSM3fr show reduced growth in Salivary Glands due to fixed mutation of MCK-2. Journal of Virology 85, 10346-10353 (2011). https://doi.org/10.1128/JVI.00545-11
Adler B, Schaadt E, Kempkes B, Zimber-Strobl U, Baier B, Bornkamm, GW. Control of Epstein-Barr virus reactivation by activated CD40 and viral latent membrane protein 1. Proceedings of the National Academy of Sciences USA 99, 437-442 (2002). https://doi.org/10.1073/pnas.221439999