Research Group Toptan

Dr. med. Tuna Toptan Grabmair
Assistenzärztin für Medizinische Mikrobiologie, Virologie und Infektionsepidemiologie

Expertise:
Tumor Virology | Polyomaviruses | Oncogenic herpesviruses | Coronaviruses 

Publications:
A full and up-to-date list of publications can be accessed via PubMed

Online profiles:
ORCID | Twitter | GoogleScholar | LinkedIn

Aims

We use in vivo and in vitro infectious model systems to study the pathogenesis of SARS-CoV-1, SARS-CoV-2, MERS-CoV, and Influenza infections (Projects 1-3). 

Our virus-related cancer model is based on the Merkel cell carcinoma caused by the Merkel cell polyomavirus (MCV). We also investigate other commensal polyomaviruses and their disease associations that occur in the context of immunosuppression (Project 4). 

Methods

Our methods also include:

  • Recombinant virus generation using BAC technology: We use recombinant bacterial artificial chromosome (BAC) technology for different projects analyzing the virus life cycle, transmission and pathogenesis, as well as to identify viral and host factors involved in these processes. We employ en passant mutagenesis to generate recombinant viruses that carry point mutations, deletions, and reporter genes to facilitate cell-based screenings for antivirals, and to monitor the efficacy of therapeutic and preventive measures.
  • Next generation sequencing (Nanopore Oxford Platform) for routine surveillance analyses and research projects
  • High throughput drug/siRNA screening using high density cell arrays 
  • 2D/3D cell culture (Coronaviruses, Influenza viruses) BSL2/3
  • In vivo mouse model system for ACLF and respiratory infections.

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Postdocs

Jeremy Nicolas de Carvalho de Sousa, PhD
Tel.: +49 69 / 6301-7162
eMail: Jeremy.deSousa@unimedizin-ffm.de
ORCID | PubMed | LinkedIn

Ask me about:
Animal Experiments | in vivo models | Immunohistochemistry | RT-qPCR 

Doctoral students

Maximilian A. Kelch, MSc
Tel.: +49 69 / 6301-86241
e-Mail: MaximilianAlexander.Kelch@unimedizin-ffm.de
LinkedIn | Twitter

Ask me about:
2D/3D cell culture | High-throughput siRNA/drug screening | Coronaviruses | RT-qPCR
 

Projects

1. iDRUG4PanCoV: Intelligent drug discovery to target pathogenic Coronaviruses (CoV)
Antivirals targeting host proteins required for the viral life cycle are less likely to result in the selection of resistant viruses. Together with collaborators in Heidelberg and Jena we seek to identify host factors essential for the pathogenesis of pandemic-related RNA virus infections and drugs combinations targeting host factors for effective treatment. Genome-wide screens published until now show limited consensus, likely due to different perturbation methods (RNAi, CRISPR/ Cas9), host cell lines, and virus isolates used. iDRUG4PanCOV aims to tackle these limitations and develop a robust high-throughput screening platform that can be rapidly implemented in case of outbreaks. Dr. Erfle’s group designs and prints high-density cell array (HDCA) plates (AG Erfle) and performs automated phenotypic data analysis using microscopy. HDCA allows parallel testing of different cell lines, virus isolates, and drugs along with numerous biological and technical replicates using the same printed plates with ~20,000 spots/plate. Dr. König’s group (AG König) uses the collected images and preprocessed data to identify host dependency factors and drugs using machine learning algorithms. Our group in Frankfurt conducts the infection experiments, drug screens, and validation of the identified host factors using functional assays in BSL3.
 

2. Role of CoV Nucleocapsid phosphorylation in virus life cycle
The LOEWE-CoroPan consortium is a newly established interdisciplinary research network initiated by the Goethe University Frankfurt, Philipps University Marburg, and Justus Liebig University Gießen. We strive to gain a comprehensive understanding of the viral and host factors involved in the pathogenesis of coronavirus infections, and to develop effective treatment strategies. Coronavirus nucleocapsid proteins play a key role in RNA synthesis, the formation of genomic RNA, and the discontinuous transcription of subgenomic mRNAs.  Phosphorylation of the nucleocapsid protein at a highly conserved arginine-serine-rich region (R/S region) plays an essential role for its multifunctionality. Together with Nadine Biedenkopf (AG Biedenkopf) we seek to identify conserved mechanisms among coronaviruses that regulate virus replication through nucleocapsid phosphorylation. 

3. The role of respiratory infections in Acute on Chronic Liver Failure (ACLF)
ACLF initiative (ACLF-I) is a newly established interdisciplinary research network initiated by the Goethe University Frankfurt, the Fraunhofer Institute for Translational Medicine and Pharmacology, the Georg-Speyer-Haus, and the Paul-Ehrlich-Institute. The ACLF Initiative comprises 14 sub-projects organized into three modules: triggers and key mechanisms, organ-specific mechanisms, and organ interactions and multidimensional models. Our project focuses on the identification and analysis of respiratory infections that may play an important role as a precipitating factor in ACLF. Given the above-average mortality-rate of ACLF patients with pneumonia, understanding these relationships is of high clinical relevance. Together with Gernot Rohde (AG Rohde) we investigate the role of respiratory infections as a potential trigger of ACLF in animal models, and also characterize the epidemiology of respiratory infections in ACLF patient cohorts.

4. Human polyomavirus-associated diseases 
Primary infections with human polyomaviruses are ubiquitous but asymptomatic, and generally occur during early childhood with seroprevalence rates ranging from 20% to 99%. Primary infection is followed by lifelong latency that is controlled by cellular and humoral immune surveillance. Impairment of this immune control by a variety of perturbations, including chronic diseases, primary or acquired immunodeficiency, immunosuppressive drugs, or transplantation, may lead to a broad spectrum of pathologies ranging from inflammatory to neoplastic. 
We are interested in studying cellular pathways involved in polyomavirus pathogenesis using oncogenic Merkel cell polyomavirus and other polyomaviruses that are known to be associated with non-neoplastic diseases in immunocompromised patients. 

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High Impact

  • Veleanu A*, Kelch MA*, Ye C, Flohr M, Wilhelm A, Widera M, Martinez-Sobrido L, Ciesek S, Toptan T. Molecular Analyses of Clinical Isolates and Recombinant SARS-CoV-2 Carrying B.1 and B.1.617.2 Spike Mutations Suggest a Potential Role of Non-Spike Mutations in Infection Kinetics. Viruses. 2022; 14(9):2017. IF 5.18
  • Toptan T, Cantrell PS, Zeng X, Liu Y, et al., Proteomic approach to discover human cancer viruses from formalin-fixed tissues. JCI Insight 2020, 5(22). IF 9.48
  • Toptan T, Abere B, Nalesnik MA, Swerdlow SH, et al., Circular DNA tumor viruses make circular RNAs. Proc Natl Acad Sci USA 2018, 115(37): E8737-E8745. IF 12.78
  • Toptan T, Yousem SA, Ho J, Matsushima Y, et al., Survey for human polyomaviruses in cancer. JCI Insight 2016, 1(2). IF 9.48
  • Kwun HJ*, Toptan T*, Ramos da Silva S, Atkins JF, et al., Human DNA tumor viruses generate alternative reading frame proteins through repeat sequence recoding. Proc Natl Acad Sci USA 2014, 111(41):E4342-4349. IF 12.78

*equal contribution

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Bachelor and Master Theses

We are seeking highly motivated Bachelor and Master degree students. If you are interested, please email your CV and a brief motivation letter to Dr. Toptan.

Doctorate and postdoctorate positions

Self-funded PhD candidates and postdoctoral fellows willing to work with us can contact Dr. Toptan. Please include your CV, a cover letter, and contact information of three references.

Current vacancies

Please apply through our online application system.