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Dr Lars Dölken

Dr Lars Dölken

Lars Dölken is accepting applications for PhD students.

Lars Dölken is available for consultancy.


Office Phone: 01223 761304

Departments

Department of Medicine:
Lecturer in Transfusion and Transplantation Virology

Research Interests

Herpesvirus are large DNA viruses which have co-evolved with their human and animal hosts for millions of years. Humans are infected with eight different herpesviruses causing a broad spectrum of disease ranging from the common cold sores to cancer. Besides encoding for >100 viral proteins they also express numerous small and large non-protein-coding RNAs to reprogramme their host cell environment for their own needs. We aim to increase our understanding of the underlying molecular mechanisms and identify new molecular targets for antiviral intervention.

Functional role of non-coding RNAs in herpesvirus infections
Although usually asymptomatic in healthy individuals, human cytomegalovirus (HCMV) is the major cause of morbidity in immunocompromised patients and allogeneic bone-marrow or organ-transplant recipients. As such, it poses an important risk factor for graft failure following heart and kidney transplantation, resulting in patient death or the need for re-transplantation. In addition, it is the leading agent of birth defects among congenitally transmitted infections affecting about 1:1,000 new-borns.

During primary infection and reactivation, HCMV encounters an array of innate and adaptive immune responses. MicroRNAs (miRNAs) represent a novel entity of viral factors counteracting these defences requiring no protein expression to exert their function. This makes them ideal, non-immunogenic tools for these viruses to regulate their own as well as host gene expression during latency and reactivation thereof.

To date, more than 80 miRNAs have been identified in six human herpesviruses – at least 11 miRNAs are expressed by HCMV. We established its murine model to study the biology and function of cytomegalovirus miRNAs (Dölken et al., J Virol 2007). Using this model, we recently identified the first phenotype of a miRNA knock-out virus in vivo (Dölken et al., PLoS Pathogens 2010). A murine cytomegalovirus mutant lacking two virally encoded miRNAs showed severe attenuation in salivary glands during subacute infection indicating an important role of these small RNA molecules in persistent infection and host-to-host virus transmission.

Employing a broad range of technologies including reverse virus genetics and high-throughput technologies (RIP-Chip and PAR-CLIP) we explore the function of herpesvirus miRNAs to answer whether they may serve as readily accessible targets for novel antiviral agents.

For different human and murine herpesviruses we apply novel RNA tagging methods to study regulation of viral gene expression as well as host cell modulation during lytic infection, latency and reactivation thereof.

Keywords

RIP-Chip ; microRNA ; viral evasion ; ChIP ; virus ; RNA and DNA FISH ; PAR-CLIP ; tagging

Topics

  • cytomegalovirus
  • human cytomegalovirus (HCMV)

Key Publications

Marcinowski L, Lidschreiber M, Windhager L, Rieder M, Bosse JB, Rädle B, Bonfert T, Györy I, de Graaf M, Prazeres da Costa O, Rosenstiel P, Friedel CC, Zimmer R, Ruzsics Z, Dölken L. Real-time transcriptional profiling of cellular and viral gene expression during lytic cytomegalovirus infection. PLoS Pathog. 2012 Sep;8(9):e1002908. doi: 10.1371/journal.ppat.1002908. Epub 2012 Sep 6.

Windhager L, Bonfert T, Burger K, Ruzsics Z, Krebs S, Kaufmann S, Malterer G, L’hernault A, Schilhabel M, Schreiber S, Rosenstiel P, Zimmer R, Eick D, Friedel CC, Dölken L. Ultra short and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution. Genome Res. 2012 Apr 26.

Marcinowski L, Tanguy M, Krmpotic A, Rädle B, Lisnić VJ, Tuddenham L, Chane-Woon-Ming B, Ruzsics Z, Erhard F, Benkartek C, Babic M, Zimmer R, Trgovcich J, Koszinowski UH, Jonjic S, Pfeffer S, Dölken L. Degradation of cellular mir-27 by a novel, highly abundant viral transcript is important for efficient virus replication in vivo. PLoS Pathog. 2012 Feb;8(2):e1002510. Epub 2012 Feb 9.

Tuddenham L, Jung JS, Chane-Woon-Ming B, Dölken L, Pfeffer S. Small RNA deep sequencing identifies microRNAs and other small noncoding RNAs from human herpesvirus 6B.J Virol. 2012 Feb;86(3):1638-49. Epub 2011 Nov 23.

Halenius A, Hauka S, Dölken L, Stindt J, Reinhard H, Wiek C, Hanenberg H, Koszinowski UH, Momburg F, Hengel H. Human Cytomegalovirus Disrupts the MHC Class I Peptide Loading Complex (PLC) and Inhibits Tapasin Gene Transcription. J Virol. 2011 Jan 19.

Miller C, Schwalb B, Maier K, Schulz D, Dümcke S, Zacher B, Mayer A, Sydow J, Marcinowski L, Dölken L*, Martin DE, Tresch A*, Cramer P*. Dynamic transcriptome analysis measures rates of mRNA synthesis and decay in yeast. Mol Syst Biol. 2011 Jan 4;7:458.

Dölken L, Krmpotic A, Kothe S, Tuddenham L, Tanguy M, Marcinowski L, Ruzsics Z, Elefant N, Altuvia Y, Margalit H, Koszinowski UH, Jonjic S, Pfeffer S. Cytomegalovirus microRNAs facilitate persistent virus infection in salivary glands. PLoS Pathog. 2010 Oct 14;6(10):e1001150.