Troels Kasper Høyer Scheel

Troels Kasper Høyer Scheel

Associate Professor

My research group investigates virus-host interactions at the molecular level. We are fascinated by viruses, and how something so small at the border of the definition of life and with very few genes can take over control of the cell, the organ or the body. With the recent COVID-19 pandemic, the importance of basic virology for development of therapeutics and vaccines need no further explanation.

Our group consists of around 10 researchers at all levels. You find us on the 13th floor at the Panum Institute. We work with around 40 other scientists within Copenhagen Hepatitis C Program (CO-HEP) and are affiliated with Department of Immunology and Microbiology, University of Copenhagen as well as Department of Infectious Diseases, Hvidovre Hospital.

Fields of interest

Our research interest is focused on the molecular and cellular biology of viral infections. My training was with hepatitis C virus (HCV), where basic research has paved the way for novel antivirals transforming therapy. Our culture systems for HCV and the use of these for functional and antiviral studies contributed heavily to this development (Scheel and Rice 2013 Nat Med). We currently in particular are interested in molecular biology of viruses and their interplay with cellular factors at the RNA level (Damas 2019 ncRNA). Previous and ongoing projects include the interactions between viruses and miRNAs or other cellular RNAs, miRNA systems biology, RNA modifications, functional and therapeutic studies of HCV, molecular evolution of RNA viruses, development of in vivo infectious clones and cell culture systems for cultivation of viruses, RNA virus recombination and novel animal homolog viruses of HCV.

Viruses of interest include HCV and related viruses, vector-borne viruses such as chikungunya, yellow fever, Zika and tick-borne encephalitis virus, animal pathogens such as pestiviruses, and emerging viruses, such as SARS-CoV-2 the virus responsible for COVID-19.

Primary fields of research

A central research focus is RNA viruses, and how these interact with cellular factors during infection. This exciting field allows for application of state-of-the art systems biology techniques in the context of viral infection.

We previously used such approaches to study micro-RNA (miRNA) interactions during viral infection. Hepatitis C virus (HCV) has been known as a unique example of a virus that critically requires a cellular miRNA through binding of the liver-specific miR-122 to the viral 5’ UTR. This interaction was previously shown to enhance viral translation, RNA stability and replication. Using cross-linking and immunoprecipitation (CLIP) of the argonaute (AGO) protein, which directly binds the miRNA and its target, we directly confirmed this interaction and further demonstrated that HCV infection functionally sequesters miR-122 (Luna 2015 Cell). This “sponge” effect of the tumor suppressor, miR-122, leads to de-repression of cellular miR-122 targets – an RNA based mechanism potentially contributing to an environment fertile for liver cancer.

A limitation of AGO-CLIP methods is the lack of experimental pairing between identified targets and the bound miRNA. Identification of miRNA-target pairs therefore relies on bioinformatic predictions. Through method optimization, we developed ways to experimentally ligate the two, thereby unambiguously identifying miRNAs and their cognate targets (Moore 2015 Nat Comm). The resulting data set generated a map of miRNA interactions in mouse brain and human liver cells. In a follow-up study in cattle cells, we generated the so far most comprehensive binding map approaching saturation (Scheel 2017 Sci Rep).

With methods available to identify unknown miRNA interactions, we asked the question whether HCV/miR-122 is a unique case? We therefore screened 15 different viral infections (Scheel 2016 Cell Host Micr). Of particular interest was that pestiviruses, important livestock pathogens, specifically bound members of the cellular miR-17 family to their 3’ UTRs. Unlike the canonical action of miRNAs down-regulating mRNAs, miR-17 binding stimulated pestiviral RNA replication. Similarly to HCV, miRNA binding was found to be critical for viral replication. We further found that pestiviral infection specifically sequestered miR-17, leading to functional de-repression of cellular genes. Nonetheless, using evolution-in-a-dish experiments and deep sequencing, we found that pestiviral miRNA tropism could be re-directed to use other or no miRNAs (Kokkonos 2020 NAR). Thus, HCV/miR-122 is not a unique case, rather pestiviruses also require binding of a cellular miRNA. We continue studies to functionally understand miRNA requirements for hepaci- and pestiviruses (Yu 2017 PLoS Pathog). Other ongoing projects focus on RNA-RNA interactions more broadly during viral infections, using methods relying on direct RNA-RNA cross-linking.

Another research focus is animal homolog viruses of HCV. Since its discovery in 1989, the origin of HCV has been a mystery and solid reports of related endemic viruses lacking. With deep sequencing approaches, this field exploded and we now know of a plethora of HCV related hepaciviruses. We were involved in discovery of several of these (Kapoor 2013 mBio; Kapoor 2013 JVI). Curiously, the closest related virus to HCV is equine hepacivirus (EqHV), which is of particular interest as a model of HCV pathology and immune responses as well as for its potential role in transmissible equine liver disease. Through construction of an infectious clone, we demonstrated the genetic make up and course of infection after intrahepatic injection into a horse (Scheel 2015 PNAS). By experimental challenge in horses we further described the typical acute resolving infection that follows, including intrahepatic transcriptomic changes to infection (Tomlinson 2021 Hepatology). We further characterized the related equine pegiviruses, and found that these target the bone marrow without causing clinical disease (Tomlinson 2020 PLoS Pathog). In ongoing collaborative studies, we continue work to understand hepaci- pegi- and parvoviruses in horses in vivo.

Rodent hepacivirus is another particularly interesting virus given its role as a small animal model for HCV. No current immune-competent animal model for HCV exists, hampering vaccine development. Together with collaborators, we characterized rat hepacivirus (RHV) in vivo (Trivedi 2018 Hepatology). We also, together with Charles Rice’ laboratory at The Rockefeller University adapted RHV to lab mice, providing an even more accessible surrogate model for HCV (Billerbeck 2017 Science). We subsequently developed in vitro systems for this virus, established assays for neutralizing antibodies and studied its entry receptor dependency (Wolfisberg 2019 J Virol; Wolfisberg 2022 Hepatology).

Teaching

Course and exam responsible for The Immune Response to Infection on the Immunology and Inflammation MSc.

Lectures and exam preparation (virology) on Immunology and Microbiology on the Human Biology MSc

Lectures and lab course (virology) on Clinical Disease Units / Microbiology experimental course for the Medicine BSc.

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