Malin Flodström-Tullberg group
Etiology and pathogenesis of Type 1 Diabetes in humans - A role for enteroviruses?
Infections with common viruses (e.g. Coxsackieviruses) have been linked to type 1 diabetes development in humans. Our present research seeks to define the role of the virus in the disease process. We focus our studies on how the virus affects the infected host and the cross-talk between the virus, the immune system and the pancreatic beta cells. We are also engaged in research aiming at finding biomarkers for beta cell destruction. We expect that our studies will generate valuable information for the design of preventative treatments against islet cell destruction and type 1 diabetes.
The group also has a strong interest in the development and testing of novel prototype vaccines for enteroviruses. Moreover, we are studying altered endocrine and immune functions in the disease Cystic Fibrosis.
Keywords: Autoimmunity, Beta cell, Coxsackievirus, Enterovirus, Innate immunity, Cystic Fibrosis, Insulin, Interferon, Islets of Langerhans, Protease, Translational Research, Type 1 Diabetes, Vaccine, Virus
Malin Flodström Tullberg, Group Leader, Ph.D. Professor
Dr. Malin Flodström Tullberg was recruited to Karolinska Institutet in 2003. She holds a Ph.D. degree in Medical Cell Biology from Uppsala University, Sweden (1998), and did a postdoc in immunology at The Scripps Research Institute, La Jolla, USA (1998-2003). Besides being professor and group leader, she is serving as deputy unit head for the Center for Infectious Medicine. She also holds a visiting professorship at the University of Tampere, Finland.
Office phone number: +46 8 524 87625 or +46 76 947 4569
Virginia Stone, B.Sc., Ph.D. Postdoc
Virginia Stone has a bachelors degree in Molecular Biology and Biochemistry from Durham University, England. She holds a Ph.D.from the Peninsula College of Medicine and Dentistry, Devon (2013). Her research now involves the possible mechanisms through which enteroviruses may contribute to the development and pathogenesis of Type 1 diabetes, with a particular focus on the gut.
Office number: +46 8 585 81158
Soile Tuomela, Ph.D. Postdoc
Soile Tuomela has a MSc degree in Genetics from University of Turku, Finland. She did her PhD studies at Turku Centre for Biotechnology, focusing on the characterization of the priming of human T helper cell differentiation. She obtained her doctoral degree from the Faculty of Medicine, University of Turku in 2013. As a postdoctoral fellow she has been engaged in the identification of Type 1 Diabetes related biomarkers using high-throughput methodology. Her current project aims at evaluating the role of genetic polymorphism in the development of Type 1 Diabetes.
Office number: +46 8 585 81158
Magdalena Mazur, Ph.D. Postdoc
Magdalena Mazur completed her Bachelor’s and Master’s degrees at Warsaw University. She did her PhD at Lund University Stem Cell Centre where she focused mostly on different aspects of pancreas development and biology. Later this continued during her post-doctoral position at AstraZeneca (Mölndal) where she was investigating novel sources of stem cells for potential diabetes treatment. In her next position as a Research Scientist in Clinical Research Centre in Malmö she was responsible was establishing a core facility for making patient-derived iPS cells. Currently, she is exploring novel ways to study the etiology and pathogenesis of type 1 diabetes, with specific focus on viral infections and their impact on the pancreatic beta cells.
Sebastian Kapell, M.Sc. Ph.D. Student
Sebastian Kapell holds a master’s degree in molecular medicine from Uppsala University, Sweden (2014). In order to combine his interests in virology and human metabolic syndromes, he joined the Flodström-Tullberg group, in order to study enteroviral infections and their potential role in type 1 diabetes. Sebastian´s research focus lies in describing the mechanisms by which an enterovirus modulates the function of the insulin secreting beta cell and how this relates to innate immunity. This information may allow for a more complete understanding of the etiology of type 1 diabetes and the factors and mechanisms that are important in disease development.
Office phone number: +46 8 585 81158
Renata Utorova, B.Sc. MD-PhD student
Renata holds a bachelor’s degree in medicine with a major in biomedicine from Karolinska Institutet (2010) and is currently enrolled in the MD-PhD program. Her research focuses on lung and metabolic function in individuals with cystic fibrosis. She studies antiviral defence mechanisms in CF with relevance for respiratory exacerbations and cystic fibrosis-related diabetes.
Erna Domsgen, Postdoc
Erna Domsgen did her postdoc in the group until 2017. She was engaged in studies related to the host immune response to picornaviruses and how such viruses evade the innate immune response. Erna keeps an affiliation to the MFT group and is currently working at Mabtech, Sweden.
Emma Svedin, Ph.D
Emma Svedin presented her thesis in 2017. Her Ph.D. studies included aspects of how enterovirus infections result in impaired beta cell functions. She was also studying why patients with cystic fibrosis have a decreased ability to clear viral and bacterial infections. Emma keeps an affiliation to the MFT group and is currently working at GE Health Care.
Pär Larsson, Ph.D
Pär Larsson worked on the mechanisms that regulate susceptibility to enterovirus-induced type 1 diabetes and with the development and testing of an enterovirus vaccine. He defended his thesis in 2014. Currently Pär is working for GE Health Care Uppsala.
Katharina Lind, Ph.D.
Katharina Lind defended her thesis in 2014. The aims of her Ph.D. studies were to determine how the host cell recognizes enteroviruses, how enteroviruses evade the host immune system and to investigate the role of type III interferons in the host immune response to enterovirus infections. Katharina is presently working at Mabtech, Sweden.
Olli Laitinen, Ph.D., Senior Researcher
Olli Laitinen holds a Ph.D. in molecular biology from the University of Jyväskylä, Finland (2001). After completing his Ph.D. and until 2012 Dr. Laitinen was Research Director at Ark Therapeutics followed by CSO at Vactech Oy. At CIM, Olli worked on projects aiming at unravelling the mechanisms by which enteroviruses cause pancreatic beta cell damage. This work involved the development of new tools to study virus-host interactions. He is currently at the Institute of BioMediTech at the University of Tampere, Finland, where he continues working on research projects started at CIM in a close collaboration with Malin Flodström-Tullberg’s group.
Terezia Pincikova, M.D., Ph.D.
Terezia Pincikova studied the impact of vitamin D supplementation on the immune response and on glucose tolerance in cystic fibrosis, and defended her thesis in 2014. The results of her research suggest that vitamin D exerts a complex immunomodulatory effect which may be clinically beneficial for cystic fibrosis patients. Terezia Pincikova is presently working as a resident in Respirology at the Akademiska hospital in Uppsala, Sweden.
Lakshmikanth Tadepally, Ph.D. Senior Research Fellow
Lakshmikanth Tadepally holds a Ph.D. in Experimental Immunology from the University of Catanzaro, Italy and Karolinska Institutet (2008). During the years 2010-2012 he worked as a Senior postdoctoral fellow in the Flodström-Tullberg lab on a vaccine development project in collaboration with Vactech Oy, Finland and Sanofi Pasteur, France. From 2012-2014 Lakshmikanth Tadepally worked in Oncology Scientific Communications at Novartis Healthcare Private Limited, Hyderabad, India. From 2014 Lakshmikanth Tadepally is Research Coordinator at the Mass Cytometry facility, SciLifeLab, Stockholm, Sweden.
Michael Hühn, Ph.D
Michael Hühn studied different aspects of the innate immune response to enteroviruses and defended his thesis in 2010. Among other things he demonstrated that the gene ifih1 (mda5) is crucial for the successful host response to enterovirus infections. He is presently a postdoctoral fellow in the laboratory of Prof. Fiona Powrie, at the University of Oxford, U.K.
Stella Jacobson, Ph.D
Stella Jacobson was working in the field of transplantation immunology and was the first to show that mesenchymal stromal cells provide protection from allograft rejection. She defended her thesis in 2010, and is currently working at the Swedish Council on Health Technology Assessment (SBU).
Monica Hultcrantz, Ph.D.
Monica Hultcrantz defended her thesis on the role of interferons in type 1 diabetes in 2008. One of her major contributions was to show how the pancreatic beta cell regulate type 1 diabetes development by responding to proinflammatory cytokines. Monica is presently working at the Swedish Council on Health Technology Assessment (SBU).
Type 1 diabetes is a chronic disease that results from a destruction of the insulin-producing pancreatic islet beta cells. The incidence of type 1 diabetes is increasing rapidly throughout the world. In Sweden the disease affects more than 1/200 people.
At present, there are no preventative treatments for Type 1 diabetes, and the high degree of transplant rejection and scarcity of beta cell material hampers islet replacement strategies. The accelerated incidence of Type 1 diabetes calls for the rapid development of preventative therapies.
Epidemiological data and clinical findings strongly suggest that infections with common cold viruses (mainly those by enteroviruses such as members of the Coxsackie B virus family, here denoted CVBs) can trigger the onset of Type 1 diabetes. Further knowledge on how virus infections affect the checkpoints and mechanisms that regulate the development of diabetes is needed for the design of preventative therapies.
Our studies focus on the cross-talk between the virus, the immune system and the pancreatic beta cells with an aim to provide an increased understanding for how virus infections may be involved in Type 1 diabetes. Our studies are performed with a translational approach, namely by combining basic mechanistic in vitro studies in cell lines and pancreatic islets from humans, with pathophysiological studies in human biological samples and in vivo model systems.
- The European Union, FP7
- The Novo Nordic Foundation
- The Strategic Research Program in Diabetes, Karolinska Institutet
- The Swedish Child Diabetes Foundation
- The Swedish Diabetes Association Research Foundation
- The Swedish Innovation Agency, VINNOVA
- The Swedish Research Council
- Erica Lederhausens Minnesfond
- The JDRF/Network for Pancreatic Organ Donors with Diabetes (nPOD)
Enteroviral proteases: structure, host interactions and pathogenicity.
Rev. Med. Virol. 2016 Jul;26(4):251-67
Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice.
Diabetologia 2013 Apr;56(4):867-74
Melanoma differentiation-associated protein-5 (MDA-5) limits early viral replication but is not essential for the induction of type 1 interferons after Coxsackievirus infection.
Virology 2010 May;401(1):42-8
The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice.
Diabetologia 2009 Feb;52(2):299-305
Co-transplantation of stromal cells interferes with the rejection of allogeneic islet grafts.
Ann. N. Y. Acad. Sci. 2008 Dec;1150():213-6
IFN-gamma production dominates the early human natural killer cell response to Coxsackievirus infection.
Cell. Microbiol. 2008 Feb;10(2):426-36
Interferons induce an antiviral state in human pancreatic islet cells.
Virology 2007 Oct;367(1):92-101
RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection.
J. Immunol. 2005 Feb;174(3):1171-7
Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse.
Diabetes 2003 Nov;52(11):2696-700
Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells.
Diabetes 2003 Aug;52(8):2025-34
Target cell defense prevents the development of diabetes after viral infection.
Nat. Immunol. 2002 Apr;3(4):373-82
A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection.
Virology 2001 Mar;281(2):205-15
We are always interested in recruiting talented PhD students and postdoctoral fellows. Please feel free to contact Dr. Malin Flodström Tullberg for further information on current opportunities.