LaborFigure 1: Epigenetic modification patterns of latent KSHV genomes

Research Areas

Tumorigenic Herpesviruses: Kaposi sarcoma-associated herpesvirus and Epstein-Barr Virus

The gamma-herpesviruses Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) are able to cause tumors in humans. Although these tumors are rare in the general population, they occur with increased frequency in immunodeficient individuals. In the wake of the AIDS pandemic, their incidence has risen dramatically such that today Kaposi sarcoma is one of the most frequent tumors in some regions of sub-saharan Africa.  

KSHV- and EBV-associated tumors are caused by latently infected cells. Such cells do not produce viral progeny, but form a reservoir of viral infection in which the viral genome persist as a nuclear episomes that only express a very limited reservoir of viral genes. A primary goal of our work is the elucidation of the molecular mechanisms that govern establishment and maintenance of viral latency. Recently, we were able to show that a hallmark of primary KSHV latency is the establishment of complex histone modification patterns and recruitment of polycomb repressor complexes, which leads to the establishment of bivalent chromatin on key lytic promoters. We strongly suspect that KSHV actively induces this chromatin state. We employ experimental infection systems together with state-of-the-art analytical methods (e.g., ChIP-seq, RNA-seq) to identify latent gene products and genetic elements that control epigenetic patterns in KSHV and related viruses. In addition, we are investigating the functions of individual latency gene products, especially viral microRNAs, during viral infection and tumorigenesis.

Tumorigenic Polyomaviruses: Merkel Cell Polyomavirus

Merkel cell carcinoma (MCC) is a rare but highly aggressive tumor that primarily afflicts the elderly or the immunosupressed. Recently, a novel polyomavirus, termed Merkel cell polyomavirus (MCPyV), was identified in MCC tissues. 80% of all MCC cases harbor monoclonally integrated, defective MCPyV genomes, strongly arguing for a causative role of abortive MCPyV infection during MCC pathogenesis. Using a synthetic consensus genome, we were able to establish a semi-permissive replication system. We now employ this system to investigate the role of T-antigens and a viral microRNA during the viral lifecycle as well as virally induced transformation, and to identify novel targets that may be exploited for therapeutic treatment of MCPyV-positive Merkel cell carcinoma. 

Detection and analysis of infectious agents by high throughput sequencing

High throughput or next generation sequencing (NGS) has a unique potential to perform comprehensive metagenomic analyses of bacterial and viral pathogens in clinical specimen. A significant advantage of this technique is the ability to detect known as well as novel infectious agents. The development of NGS-based pathogen detection methods thus may contribute significantly to the ability to rapidly and efficiently react to future outbreaks. In order to optimally exploit the potential of this technology, we analyze different diagnostic entities by next generation sequencing with Illumina MiSeq and HiSeq 2500 machines, and systematically compare the results to conventional PCR-based detection methods. In addition, we are developing innovative bioinformatic solutions for the analysis of complex metagenomic data from clinical specimen.

 

Figure 2: Predicted RNA secondary structure of a synthetically produced molecule for the simultaneous expression of all KSHV coded microRNAs.