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Studies of sever bacterial infections using organotypic human disease models

Our overall goal is to identify inflammatory traits that lead to the failure of tissue to maintain its integrity and function in human infectious and inflammatory diseases. The research focuses on identifying bacterial-induced responses that shape myeloid immune cell functions in tissue and thereby contribute to disease susceptibility, progression, and outcome.

Our research aims to:

  • Develop customized human organotypic models for disease mechanism identification, biomarker detection, and validation of interventions in sever bacterial infectious diseases
  • Utilize identified disease mechanisms to develop tailored therapy and implement personalized medicine in sever infectious diseases. 
  • Identify central host-derived mediators in pathogenic events induced by bacterial exotoxins.

Of particular interest are the two Gram-positive bacteria Streptococcus pyogenes and Staphylococcus aureus, both of which may cause highly aggressive invasive infections such as toxic shock, necrotizing pneumonia and necrotizing fasciitis that are associated with substantial morbidity and mortality. Studying the many processes involved in shaping inflammatory responses and pathogenesis at the tissue site in human infectious diseases are difficult. Our approach of developing and using human multicellular three-dimensional (3D) tissue models, so called organotypic models, with myeloid immune cells and that mimic real tissues, provides unique tools to study host-pathogen interactions contributing to local immune responses and pathology

Keywords: Infection, inflammation, myeloid immune cells, human organotypic models, personalized medicine

Members

Mattias Svensson, MSc, PhD, Associate Professor
Expertise in preclinical research in the field of immunology and infection, myeloid immune cells, host pathogen interactions, and tissue biology. Main responsibility to create a milieu where excellent scientific progress can be made and ensure that doctoral students receive a high-quality doctoral education and post docs get good quality supervision to develop their scientific independence.
Phone: +46 8 524 837 73
Email: mattias.svensson@ki.se

Puran Chen, MD, PhD-student

Egle Kvedaraite, MD, PhD-student

Afzal Muhammad, PhD., post doc.

Majda Dzidic, PhD; postdoc

Magdalini Lourda, PhD; Assistant professor

Victoria Vassen, PhD; postdoc (from August 2019)

Former members of the group

Julius Juarez, PhD, postdoctoral studies completed 2013

Anh Thu Nguyen Hoang, PhD-studies completed 2013

Nikolai Siemens, PhD, postdoctoral studies completed 2016

Sofia Björnfot-Holmström, DDS, PhD-studies completed 2017

Takeaki Wajima, PhD, postdoctoral studies completed 2017

    Recent and ongoing projects

    INFECT-project, 2013-2018
    Supported by FP7 Health

    The INFECT-project included 14 partners from across Europe, Israel and the US. The overall goal of the project was to advance our understanding of the pathophysiological mechanisms, prognosis, and diagnosis of the multifactorial highly lethal necrotizing soft tissue infections (NSTIs). NSTI’s are rapidly spreading infections that may cause extensive soft tissue or limb loss, multiorgan failure and are associated with a considerable fatality rate. There is an urgent need for novel diagnostic and therapeutic strategies in order to improve outcome of NSTIs. To achieve this, a comprehensive and integrated knowledge of diagnostic features, causative microbial agent, treatment strategies, and pathogenic mechanisms (host and bacterial disease traits and their underlying interaction network) was sought. INFECT obtained such insights through an integrated systems biology approach in patients and different clinically relevant experimental models.  A key achievement of INFECT was the enrollment of NSTI patients and the creation of the world’s largest patient cohort and associated biobank. Analyses of the comprehensive clinical registry generated an advanced understanding of these patients and underlying disease mechanisms.

    Personalized Medicine in Infectious Diseases

    The INFECT clinical registry and biobank now offer a resource for recently started multinational projects, PerAID and PERMIT, building on the advances made through the systems medicine approach to achieve personalized medicine in infectious diseases. The two projects are ambitious covering both severe soft tissue infections and the large heterogeneous group of sepsis. Activities range from establishment of a Nordic platform for personalized medicine in infections, to translational research aimed to identify disease signatures and biomarkers that can be used for individualized therapy, to development of clinical decision support tools.

    Unraveling tissue-specific pathways controlling human monocyte and neutrophil functions in response to bacterial toxins

    This project focuses on elucidating mechanisms by which pore-forming toxins contribute to staphylococcal pneumonia through immunomodulatory activities in the lung. Specifically, we will use our unique human organotypic lung model, combined with human monocytes and neutrophils, and samples from S. aureus infected patients. Technologies used include: multicolor confocal and flow cytometry, single cell gene expression, metabolomics and protein profiling. These studies will contribute to detect mechanisms underlying S. aureus-mediated immunomodulation in lung tissue and identify risk factors to develop severe pneumonia. Long-term this forms the basis to develop new diagnostic and treatment strategies, and the identification of toxin-induced responses may also be exploited to treat other serious lung diseases.

    Key Collaborators

    Anna Norrby-Teglund, Professor in medical microbial pathogenesis, Karolinska Institutet, Coordinator of the INFECT, PerAID and PerMIT projects

    Kristoffer Strålin, MD, PhD, Associate Professor. Specialist in Infectious Diseases, Karolinska University Hospital

    Teresa Frisan, Professor in Cell and Molecular Biology at Umeå University

    Steinar Skrede, University of Bergen, Norway

    Ole Hyldegaard, Rigshospitalet and University of Copenhagen, Denmark

    Edoardo Saccenti, Wageningen University and Research, the Netherlands

    Vitor Martin dos Santos, WUR and LifeGlimmer, Berlin, Germany

    Jan-Kristian Damås and Erik Solligård, St Olav’s Hospital and NTNU, Trondheim, Norway

    Annebeth de Vries, Red Cross, the Netherlands

    Suba Nookala, University of North Dakota, USA

    Annelies Zinkernagel, University of Zürich, Switzerland

    Financial support

    • European Commission FP7-Health
    • Swedish Research Council
    • VINNOVA
    • Karolinska Institutet

    Selected publications

    Necrotizing Soft Tissue Infections S.aureus - but not S.pyogenes- isolates display high rate of internalization and cytotoxicity toward human myoblasts.
    Baude J, Bastien S, Gillet Y, Leblanc P, Itzek A, Tristan A, et al
    J. Infect. Dis. 2019 Apr;():

    MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation.
    Holmström SB, Lira-Junior R, Zwicker S, Majster M, Gustafsson A, Åkerman S, et al
    Cytokine 2019 Jan;113():155-161

    Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.
    Emgård J, Kammoun H, García-Cassani B, Chesné J, Parigi SM, Jacob JM, et al
    Immunity 2018 01;48(1):120-132.e8

    Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis.
    Björnfot Holmström S, Clark R, Zwicker S, Bureik D, Kvedaraite E, Bernasconi E, et al
    J. Immunol. 2017 12;199(12):4023-4035

    Biofilm in group A streptococcal necrotizing soft tissue infections.
    Siemens N, Chakrakodi B, Shambat SM, Morgan M, Bergsten H, Hyldegaard O, et al
    JCI Insight 2016 07;1(10):e87882

    Adsorptive depletion of blood monocytes reduces the levels of circulating interleukin-17A in Langerhans cell histiocytosis.
    Lourda M, Olsson-Åkefeldt S, Gavhed D, Axdorph Nygell U, Berlin G, Laurencikas E, et al
    Blood 2016 09;128(9):1302-5

    Tissue-infiltrating neutrophils represent the main source of IL-23 in the colon of patients with IBD.
    Kvedaraite E, Lourda M, Ideström M, Chen P, Olsson-Åkefeldt S, Forkel M, et al
    Gut 2016 10;65(10):1632-41

    Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology.
    Mairpady Shambat S, Chen P, Nguyen Hoang AT, Bergsten H, Vandenesch F, Siemens N, et al
    Dis Model Mech 2015 Nov;8(11):1413-25

    Pulmonary tuberculosis patients with a vitamin D deficiency demonstrate low local expression of the antimicrobial peptide LL-37 but enhanced FoxP3+ regulatory T cells and IgG-secreting cells.
    Rahman S, Rehn A, Rahman J, Andersson J, Svensson M, Brighenti S
    Clin. Immunol. 2015 Feb;156(2):85-97

    Technical advance: live-imaging analysis of human dendritic cell migrating behavior under the influence of immune-stimulating reagents in an organotypic model of lung.
    Nguyen Hoang AT, Chen P, Björnfot S, Högstrand K, Lock JG, Grandien A, et al
    J. Leukoc. Biol. 2014 Sep;96(3):481-9

    Open positions

    We always want to get in touch with talented potential co-workers. If you are interested in doing research within our group, as a degree project or as a researcher, please contact the group leader Mattias Svensson, mattias.svensson@ki.se