Principal Investigator:

The role of interferon-dependent JAK-STAT
signalling for adaptive immune responses
against cytomegaloviruses

Human cytomegalovirus (CMV) is a ubiquitous betaherpesvirus, which causes mortality and morbidity in individuals with insufficient immunity (e.g., HIV/AIDS patients, transplant recipients, and congenitally infected infants).

One immediate host response to infections is the secretion of antiviral interferons (IFN). Usually, IFNs induce an antiviral state. The underlying transcriptional change is mediated by STAT transcription factors. Our group found that CMVs (human, mouse, and rat CMV) counteract IFN signaling by proteasomal degradation of STAT2. A mouse CMV mutant lacking its STAT2 antagonist is highly susceptible to IFNs and severely attenuated in vivo. Intriguingly, the mutant can serve as live attenuated vaccine against CMV and as vector platform for the vaccination against other viruses.

In the proposed project, the concept of live attenuated vaccines based on CMVs lacking IFN antagonists will be further developed and the immunological determinants of protection shall be defined.

Publications

Le-Trilling VTK, Trilling M. Mouse newborn cells allow highly productive mouse cytomegalovirus replication, constituting a novel convenient primary cell culture system. PLoS One. 2017; 12(3):e0174695.

Le-Trilling VTK, Megger DA, Katschinski B, Landsberg CD, Rückborn MU, Tao S, Krawczyk A, Bayer W, Drexler I, Tenbusch M, Sitek B, Trilling M. Broad and potent antiviral activity of the NAE inhibitor MLN4924. Sci Rep. 2016; 6:19977.

Trilling M, Le VTK, Rashidi-Alavijeh J, Katschinski B, Scheller J, Rose-John S, Androsiac GE, Jonjic S, Poli V, Pfeffer K, Hengel H. "Activated" STAT proteins: a paradoxical consequence of inhibited JAK-STAT signaling in cytomegalovirus-infected cells. J Immunol. 2014; 192(1):447-58.

Trilling M*, Bellora N*, Rutkowski AJ, de Graaf M, Dickinson P, Robertson K, Prazeres da Costa O, Ghazal P, Friedel CC, Albà MM, Dölken L. Deciphering the modulation of gene expression by type I and II interferons combining 4sU-tagging, translational arrest and in silico promoter analysis. Nucleic Acids Res. 2013; 41(17):8107-25. (*contributed equally)

Corrales-Aguilar E, Trilling M, Reinhard H, Mercé-Maldonado E, Widera M, Schaal H, Zimmermann A, Mandelboim O, Hengel H. A novel assay for detecting virus-specific antibodies triggering activation of Fcγ receptors. J Immunol Methods 2013; 387(1-2):21-35.

Trilling M, Le VTK, Fiedler M, Zimmermann A, Bleifuss E, Hengel H. Identification of DNA-damage DNA-binding protein 1 as a conditional essential factor for cytomegalovirus replication in interferon-γ-stimulated cells. PLoS Pathog. 2011; 7(6):e1002069.

Reinhard H, Le VTK, Ohlin M, Hengel H*, Trilling M*. Exploitation of herpesviral transactivation allows quantitative reporter gene-based assessment of virus entry and neutralization. PLoS One. 2011; 6(1):e14532. (*contributed equally)

Trilling M, Le VTK, Zimmermann A, Ludwig H, Pfeffer K, Sutter G, Smith GL, Hengel H. Gamma interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts. J Virol. 2009; 83(8):3684-95.

Le VTK*, Trilling M*, Wilborn M, Hengel H, Zimmermann A. Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation. J Gen Virol. 2008; 89(Pt 10):2416-26. (*contributed equally)