Malin Flodström-Tullberg group - Etiology and pathogenesis of type 1 diabetes

Type 1 diabetes is a common, chronic and life-threatening disease. Our research focuses on etiology, disease interception and early biomarkers.

Collage of photos of people on black background.
The Malin Flodström-Tullberg research group at CIM, MedH. Photo: Peter Holgersson

About our research

Type 1 diabetes is the most common, chronic and life-threatening disease in children. About 1/200 people suffer from the disease in Sweden. Malin Flodström-Tullberg's research group focuses on understanding the etiology and pathogenesis of the disease. The research group is engaged in finding disease causes and contributing to the development and preclinical testing of new disease interventions.

The group studies genetic, environmental and pancreatic beta cell intrinsic factors and how these affect the immune system and contribute to disease development. Of particular interest is the role of the environment including microbial diversity and infections with common viruses, so-called enteroviruses, in the disease process. The group has participated in the generation of and performed preclinical tests of new enterovirus vaccines which are now in phase I trials. In recent years, the group has become interested in disease biomarkers, in particular non-invasive measures to detect beta cell damage, and has built a strong platform for such studies.

The group is also 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.

Meet Professor Malin Flodström-Tullberg

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Group leader

H7 Department of Medicine, Huddinge

Group leader, Dr. Malin Flodström-Tullberg is Professor and Deputy Unit Head for the Center for Infectious Medicine (CIM). Malin was recruited to Karolinska Institutet in 2003. 

Malin holds a Ph.D. degree in Medical Cell Biology from Uppsala University, Sweden (1998). She did a postdoc in immunology at The Scripps Research Institute, La Jolla, USA (1998-2003).

Lab members

Virginia Stone

Research Specialist
H7 Department of Medicine, Huddinge

Virginia Stone's research involves the development and preclinical testing of enterovirus vaccines and antivirals. She is also engaged in studies aimed at finding early biomarkers for type 1 diabetes and how the microbiome influences diabetes risk.

Virginia 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).

Emma Ringqvist

Research Specialist
H7 Department of Medicine, Huddinge

Emma Ringqvist assists with techniques and coordinates the immunology research in the group. Her main focus is on the role of interferons in type 1 diabetes and how the environment regulates the risk of developing type 1 diabetes. 

Emma received her PhD from Uppsala University in 2010 on host-parasite interactions during Giardia infections. Over several postdoc positions she changed fields to helminth infection responses and pulmonary medicine and immunology (Massey university/ New Zealand, University of Edinburgh/Scotland, and Karolinska institutet).

The last couple of years she focused on human neonate pulmonary development and immunology, and specifically the ontogeny, development and function of pulmonary macrophages and their link to adult respiratory disease, eg. BPD and COPD.

Anirudra Parajuli

Postdoctoral researcher
H7 Department of Medicine, Huddinge

Anirudra Parajuli's current research focuses on understanding the way genetic and environmental factors, including the living environment, regulate the risk for Type 1 Diabetes development.

Anirudra has a Bachelor’s Degree in Pharmaceutical Science from Pokhara University, Nepal. He did his Masters in Pharmaceutical biotechnology and PhD in Environmental ecology (Microbiology) at the University of Helsinki, Finland.

In his PhD thesis, Anirudra investigated interactions between the microbiota in the living environment and the composition of the human gut microbiota.

Marta Butrym

PhD student
H7 Department of Medicine, Huddinge

Marta Butrym is currently working on in vitro and in vivo models to examine whether new enterovirus vaccines and antiviral treatments can prevent infections and clinically relevant diseases induced by enterovirus infections including type 1 diabetes.

Marta holds a Master’s degree in Biology from University of Warsaw, Poland. She has both academic and industry experience and has previously contributed to the pre-clinical evaluation of an antimicrobial and anti-inflammatory peptide as a drug candidate and medical device active component.

Selina Parvin

Biomedical scientist
H7 Department of Medicine, Huddinge

Selina Parvin joined the Flodström-Tullberg group in 2020 and has responsibility for genotyping, tissue sectioning, histology and cell culture work. 

Selina is a skilled laboratory technician who has worked at Karolinska Institutet for several years, and before that at Uppsala University.

Fabian Byvald

PhD student
H7 Department of Medicine, Huddinge

Fabian Byvald’s research focuses on identifying disease biomarkers and testing new antiviral treatments in preventing virus-induced beta cell damage. 

Fabian holds a Master’s degree in molecular biology from Gothenburg University, Gothenburg, Sweden.

Open positions

We are always interested in recruiting talented PhD students and postdoctoral fellows. Feel free to contact Group leader Malin Flodström-Tullberg for further information on current opportunities.

Past members

Martha Castro, Fulbright Scholar
Martha Castro was a U.S. Fulbright Scholar in the Flodström-Tullberg group 2021-2022. She studied how drugs used to treat autoimmune and inflammatory diseases affect the host's antiviral defence mechanisms in the intestine. 

Isabel Diaz Lozano, Postdoc
Isabel Maria Diaz Lozano's research involved the search for new biomarkers that relate to infections by enteroviruses and the development of type 1 diabetes. A special focus was to perform proteomic and transcriptomic studies on extracellular vesicles released in experimental model systems.

Magdalena Mazur, Ph.D., Research Coordinator
Magdalena Mazur coordinated research related to finding 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 cell. 

Kylie Burdsall, Fulbright Scholar
Kylie Burdsall was a U.S. Fulbright Scholar in the Flodström-Tullberg group 2019-2020. She focused on uncovering new biomarkers indicative of virus-induced cell damage to better understand type 1 diabetes disease progression.

Renata Utorova, Ph.D. 
Renata defended her licentiate degree in 2020 on antiviral defence mechanisms in CF with relevance for respiratory exacerbations and cystic-fibrosis related diabetes. 

Helena Sork, Postdoc
Helena Sork did a postdoc in the Flodström-Tullberg group 2018-2019 and worked on the identification of biomarkers related to enterovirus infection and its association to type 1 diabetes development.

Soile Tuomela, Postdoc
Soile Tuomela's postdoc period was funded by the Novo Nordisk Postdoctoral Fellowship Program at Karolinska Institutet. Her studies included the identification of enterovirus peptides presented by pancreatic beta cells via MHC class I. She was also involved in examining the role of genetic polymorphism in the development of Type 1 Diabetes.

Sebastian Kapell, Ph.D.
Sebastian Kapell defended his thesis in 2019. He was involved in research that focuses on describing the mechanisms by which an enterovirus modulates the function of the insulin secreting beta cell and how this relates to innate immunity.

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.

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.

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.

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.

Olli Laitinen, Ph.D., Senior Researcher
Olli Laitinen 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.

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 immuno-modulatory effect which may be clinically beneficial for cystic fibrosis patients.

Lakshmikanth Tadepally, Ph.D. Senior Research Fellow
During the years 2010-2012 Lakshmikanth Tadepally 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. His contributions included the first preclinical safety testing of a Coxsackievirus B1 vaccine in NOD mice.

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.

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.

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.

Collaborations

Karolinska Institutet

National

  • Lena Eliasson, Department of Clinical Sciences, Lund University.

International

  • Aki Sinkkonen, University of Helsinki, Finland
  • Charles Rice, Rockefeller University, New York, US
  • Heikki Hyöty, University of Tampere, Finland
  • Ivan Gerling, University of Tennessee, US
  • Minna Hankaniemi, University of Tampere, Finland
  • Noel Morgan, University of Exeter, UK
  • Roberto Mallone, Institut Cochine, Paris, France
  • Sarah Richardson, University of Exeter, UK
  • Varpu Marjumäki, University of Jyväskylä, Finland
  • Vesa Hytönen, University of Tampere, Finland

Network for Pancreatic Organ Donors with Diabetes

nPOD-virus group

Projects

The group is actively running several projects, many of which are in collaboration with other national and international research groups.

The main projects of the research group are:

  • The role of interferons in the pathogenesis of type 1 diabetes.
  • Defining the mechanism behind Coxsackievirus induced pancreatic beta cell damage and discovering new biomarkers for type 1 diabetes.
  • Development and testing of enterovirus vaccines and antivirals.
  • Understanding altered endocrine and immune functions in Cystic Fibrosis.

Research support

  • Swedish Research Council (VR)
  • The Swedish Child Diabetes Foundation (Barndiabetesfonden)
  • The Swedish Diabetes Foundation (Diabetesfonden)
  • The Swedish Heart and Lung Foundation (Hjärt-Lungfonden)
  • Riksförbundet Cystisk Fibros & Erika Lederhausens Minnesstiftelse
  • JDRF (SRA, nPOD-V)
  • Novo Nordic Foundation Denmark 

Selected publications

Link to all publications (PubMed)

  1. Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect.
    Stone VM, Butrym M, Hankaniemi MM, Sioofy-Khojine AB, Hytönen VP, Hyöty H, Flodström-Tullberg MDiabetes 2021 Sep;(): PMID: 34497136
     
  2. A hexavalent Coxsackievirus B vaccine is highly immunogenic and has a strong protective capacity in mice and nonhuman primates. 
    Stone VM, Hankaniemi MM, Laitinen OH, Sioofy-Khojine AB, Lin A, Diaz Lozano IM, Mazur MA, Marjomäki V, Loré K, Hyöty H, Hytönen VP, Flodström-Tullberg M
    Sci Adv 2020 May;6(19):eaaz2433 PMID: 32494709
     
  3. A Coxsackievirus B vaccine protects against virus-induced diabetes in an experimental mouse model of type 1 diabetes.
    Stone VM, Hankaniemi MM, Svedin E, Sioofy-Khojine A, Oikarinen S, Hyöty H, Laitinen OH, Hytönen VP, Flodström-Tullberg M
    Diabetologia 2018 02;61(2):476-481 PMID: 29151123
     
  4. A Link Between a Common Mutation in CFTR and Impaired Innate and Adaptive Viral Defense.
    Svedin E, Utorova R, Hühn MH, Larsson PG, Stone VM, Garimella M, Lind K, Hägglöf T, Pincikova T, Laitinen OH, McInerney GM, Scholte B, Hjelte L, Karlsson MCI, Flodström-Tullberg M
    J Infect Dis 2017 12;216(10):1308-1317 PMID: 28968805
     
  5. Coxsackievirus counters the host innate immune response by blocking type III interferon expression.
    Lind K, Svedin E, Domsgen E, Kapell S, Laitinen OH, Moll M, Flodström-Tullberg M
    J Gen Virol 2016 06;97(6):1368-1380 PMID: 26935471
     
  6. A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models.
    Larsson PG, Lakshmikanth T, Laitinen OH, Utorova R, Jacobson S, Oikarinen M, Domsgen E, Koivunen MR, Chaux P, Devard N, Lecouturier V, Almond J, Knip M, Hyöty H, Flodström-Tullberg M
    Diabetologia 2015 Feb;58(2):346-54 PMID: 25370797
     
  7. Induction of an antiviral state and attenuated coxsackievirus replication in type III interferon-treated primary human pancreatic islets.
    Lind K, Richardson SJ, Leete P, Morgan NG, Korsgren O, Flodström-Tullberg M
    J Virol 2013 Jul;87(13):7646-54 PMID: 23637411
     
  8. Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice.
    Larsson PG, Lakshmikanth T, Svedin E, King C, Flodström-Tullberg M
    Diabetologia 2013 Apr;56(4):867-74 PMID: 23344730
     
  9. The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice.
    Hultcrantz M, Jacobson S, Hill NJ, Santamaria P, Flodström-Tullberg M
    Diabetologia 2009 Feb;52(2):299-305 PMID: 19031069
     
  10. Target cell defense prevents the development of diabetes after viral infection.
    Flodström M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N
    Nat Immunol 2002 Apr;3(4):373-82 PMID: 11919579