Research group Anna Smed Sörensen
Mapping dendritic cells in human pulmonary viral infection and inflammation
With every breath we expose our lungs to foreign material that our immune system needs to tolerize or fight. Therefore it may not be surprising that acute respiratory infections caused by inhaled viruses such as Influenza or Hanta viruses are the most frequent reason for medical consultations in the world, and these infections are a major cause of morbidity and mortality also in Sweden. Furthermore, inflammatory pulmonary diseases such as sarcoidosis result in higher mortality than that of the general population. Potent immune responses are critical to clear infection but also drive disease progress. A more detailed understanding of the initiation and regulation of immunity in these disease conditions is central to our capacity to advance prevention and treatment. Dendritic cells (DCs) are immune cells with the unique capacity to activate naive T cells and thereby initiate adaptive immune responses. Our research aims to understand the function/dysfunction of respiratory DCs in the airways and lungs in different pulmonary disease conditions.
Infection or inflammation is often restricted to a particular site in the body and DCs are different depending on their anatomical distribution. Therefore, an important originality of our work is that we study immune cells of the respiratory system, the site of infection and inflammation. We work in close collaboration with physicians to collect endobronchial biopsies and bronchoalveolar lavage fluid and cells following bronchoscopy, as well as blood, and apply a range of sophisticated immunological and cell biological methods to understand the detailed function of DCs. If we can correlate the phenotype and function of DCs, the immune cells that present antigen to T cells, to clinical parameters, this project could aid in the identification of novel biomarkers, as well as prepare ground for new treatments for pulmonary conditions.
|Anna Smed Sörensen||Associate professor, group leader|
+46 (0)73-712 16 41 or +46 (0)8 517 768 29
Anna did her undergraduate M.Sc. studies in Molecular Biology at Uppsala universitet. She received her PhD in Experimental Medicine from Karolinska Institutet in 2004 and thereafter did postdoctoral training at Yale University School of Medicine, New Haven, CT, USA and Genentech, Inc., South San Francisco, CA, USA. She returned to Karolinska Institutet in 2010 as assistant professor supported by a Marie Curie/Vinnmer fellowhip from Vinnova. In 2014 she was recruited to the Department of Medicine Solna as a group leader.
Sang Liu has an M.D degree in Medicine from Huazhong University of Science and Technology in China and received her Ph.D in Immunology 2015 from Karolinska Institutet. She joined our group as a postdoctoral fellow in 2016, and is the recipient of postdoctoral scholarship from Barncancerfonden.
|Sindhu Vangeti||PhD student|
+46 (0)8 517 766 98
Sindhu has a B.Sc. in Microbiology and Biochemistry from the University of Mumbai, a Diploma in Forensics Science from St. Xavier's College, India. She graduated with M.Sc. degree in Virology from the National Institute of Virology and the University of Pune, India in 2011. Sindhu worked at the National University of Singapore for two years before she joined our group. Sindhu was selected for a KID PhD funded position to pursue doctoral studies and has been a PhD student in our group since 2015.
|Rico Lepzien||PhD Student|
+46 (0)8 517 766 98
Rico has a B.Sc. in Medical Biotechnology from the University of Rostock and a M.Sc. in Molecular Medicine at University of Göttingen, Germany. Rico was selected for a KID PhD funded position to pursue doctoral studies and has been a PhD student in our group since 2015.
|Meng Yu|| |
+46 (0)7 629 43 116
Meng Yu has a B.Sc. in Biological Sciences from the Jiaying University and a M.Sc. in Veterinary Medicine at South China Agriculture University, China. He is the recipient of a scholarship from the China Scholarship Council to perform his PhD studies in our group since 2016.
Sara is a 5th year Medical student at the Karolinska Institutet. She was selected for a research project in 2016-2017, and remains associated with the lab. She assists in ongoing projects on Influenza virus infections in patients.
Tomas is a postdoc at the Department of Virology, University of Helsinki. He collaborates with us on ongoing studies on the role of mononuclear phagocytes during human Hantavirus infections.
Phone: 050 448 28 66
Address: PL 21 (Haartmaninkatu 3), 00014 HELSINGIN YLIOPISTO
Klara Lenart, Master student KI Biomedicine Program
Roosa Vaitiniemi, Medical student KI Medical Program (4year)
Elisa Martini, PhD student (main supervisor: Liv Eidsmo).
Kimia Maleki, PhD student (main supervisor: Jonas Klingström)
Elza Evren, PhD student (main supervisor: Tim Willinger)
Jens Gertow, PhD. 2013-2015
Saskia Shcolz PhD. 2012-2014
Faezzah Baharom PhD. 2016-2017
Susanna Bächle, PhD. 2010-2015. (Main supervisor: Markus Moll).
Faezzah Baharom, PhD. 2012-2016. (Main supervisor: Anna Smed Sörensen).
Andrea Bieder, Master student 2011.
Maria Hellmér, Bachelor student 2011.
Gustaf Lindgren, Research summer school for medical students 2011.
Renata Utorova, Bachelor student 2011.
Abdi Farah, Summer research school student 2013.
Julia Volz, Master student 2013.
Joel Ågren, Master student 2014.
Oliver Thomas, Master student 2015.
Karin Wahlberg, Bachelor student 2015.
Kevin Fallahi, Medical student 2016.
Hanna Lindén, Rays sholar student 2016.
Adeline Mawa, Master student 2016.
Juliane Poelchen, Master student 2017.
Karolinska Institutet, Sweden
Drs. Hans-Gustaf Ljunggren, Jonas Klingström
Johan Grunewald, Anders Eklund, Karin Loré and Liv Eidsmo.
Jakob Mikaelson, Nicole Marquardt.
Karolinska University Hospital, Sweden
Dr. Danielle Friberg
Umeå universitet, Sweden
Drs. Clas Ahlm and Anders Blomberg.
Drs. Alexander Ahlberg, Magnus Starkhammar.
Genentech, Inc, USA
Drs. Ira Mellman and Cécile Chalouni.
University of Helsinki, Finland
Antti Vaheri, Tomas Strandin
Dendritic cells in the respiratory system of healthy individuals
We currently possess a good understanding of which DC subsets circulate in human blood. However, whether the same DC subsets are also found in other, less accessible human tissues such as the respiratory system, is much less clear. In fact, the details of human DC diversity and complexity are only starting to unravel and it is becoming increasingly clear that DC subsets differ depending on their anatomical location. It is especially important to assess how comparable these compartments are when studying infections and inflammatory conditions primarily affecting the respiratory system, to know whether it is justifiable in certain experimental settings to use blood DCs. In this project, we investigate what DC subsets and immune cells are found in human airways and lung as compared to blood under steady state conditions. Healthy volunteers undergo bronchoscopy and cells from bronchial wash, bronchoalveolar lavage and endobronchial biopsies as well as blood are collected for functional and phenotypical analysis.
The effect of Influenza A virus infection on human dendritic cells
Influenza or "flu" is one of the most common diseases known to mankind, caused by Influenza A virus (IAV). We are interested in how DCs are affected by IAV infection in vitro and in vivo. A backbone of our research is the utilization of protocols and experimental systems to differentiate or isolate human DCs from blood and tissues and study them in vitro. We recently showed that different myeloid DC subsets from the blood play distinct roles during IAV infection as they have different capacities to induce an antiviral response upon maturation. Next, we are investigating how tonsillar DCs at the site of infection handle the virus in vitro. Plasmacytoid DCs (PDCs) have important antiviral functions as potent producers of type I Interferons that exert transcriptional control over hundreds of interferon-stimulated genes (ISGs). We are comparing how tonsillar and blood PDCs respond to in vitro IAV exposure, and how their function is influenced by the presence of IAV. This ex-vivo setup could help provide a glimpse into tissue-resident DC behavior in the context of IAV infection.
Influenza A virus entry in a human plasmacytoid dendritic cell. Influenza A virus (green), cell surface, MHC class II (red) and cell nucleus (blue). 3D reconstruction
Mononuclear phagocytes during human Influenza A virus infections
In contrast to the wealth of knowledge generated from in vitro studies on Influenza, much less is known about the role of DCs and monocytes at the site of infection, during ongoing IAV infections. Recent studies have started to describe infiltration of innate cells to the nasal mucosa in respiratory virus infections, imploring the need for further exploration. To address this, we are currently investigating the composition and function of DC and monocyte subsets in patients with confirmed IAV infection. Our methods enable detailed phenotypic characterization of DCs and monocytes, from blood and the nasopharynx, which is the initial site of IAV infection; as well as a comparison between acute and convalescent phases of infection. Additional analyses will quantify cytokine production and antigen-specific adaptive responses. Detailed clinical characterization of patients will allow correlations between immune status and disease severity. Immunological profiles generated from this study would better reflect the complexity of IAV pathogenesis. Defining what constitutes a protective vs pathological immune response at disease presentation, by assessing local and systemic immune profiles may provide new therapeutic approaches for improving disease outcomes. The data generated will improve our knowledge on human mucosal respiratory immunology and our understanding of influenza virus pathology.
Dendritic cells in lung and blood during Hantavirus infection
We also study Hantaviruses, that have rodents as their natural host in which they induce long-lasting, asymptomatic infection. However, the virus can transfer to humans by inhalation of excreted virions in rodent waste products and cause severe and often fatal disease, including hemorrhagic fever with renal syndrome. In Sweden, Puumala virus (PUUV) is the endemic hantavirus strain, which uses bank voles (sorkar) as its reservoir. Nephropathia epidemica (“sorkfeber”) caused by PUUV, is a large public health issue in Northern Sweden. Hantavirus infection impacts effector immune cells such as NK cells and cytotoxic T cells, but very little is known on how/if the infection affects immune cells needed to initiate adaptive immune responses: DCs.
We receive lung biopsies and longitudinal blood samples from patients with acute and convalescent Hantavirus infection that we have analyzed using immunohistochemistry and multi-parameter flow cytometry, with a particular focus on DC subsets, to assess whether DCs are affected during Hantavirus infection. In addition, we have established experimental in vitro systems to study the effect of Hantavirus infection of human DCs. To investigate this, we isolate DCs from healthy blood donors and infect the DCs with different strains of Hantavirus in vitro, allowing for detailed studies of the underlying mechanism of our in vivo findings. Our findings suggest redistribution of DCs and monocytes from blood to lungs in patients suffering from PUUV infection, which normalized during convalescence, indicative of local immune activation in the lungs and airways of patients with Hantavirus infection.
Dendritic cells and regulation of immunity in sarcoidosis patients.
Sarcoidosis is a multisystem disorder forming granulomas as an immune response to either self-antigens or to microbial/environmental antigens. Since the lungs and the lung-draining lymph nodes are affected in the vast majority of sarcoidosis patients, bronchoscopies are recommended to collect endobronchial biopsies and cells lining the respiratory mucosa (using bronchoalveolar lavage fluid, or BALF) for diagnosis. It is well established that T cells are involved in the inflammation seen in sarcoidosis. The role of DCs in sarcoidosis is only starting to unfold but the working model is that peripheral DCs take up antigenic material, migrate to draining lymph nodes and present the antigen to T cells. The activated T cells then migrate back to the lung and produce disease-specific proinflammatory cytokines and chemokines that drive inflammation and disease. Despite the necessity for DCs to activate naive T cells, only limited data is available on the potential involvement of DCs in the immunopathogenesis of sarcoidosis. Also, it is well established that macrophages contribute to cytokine production in sarcoidosis but to what extend DCs are involved in the inflammatory process is yet unknown. In this project, we study DCs found in endobronchial biopsies, BAL, the lung-draining lymph node and blood samples from sarcoidosis patients. We assess their functional capacity by determining their ability to capture and present antigen to T cells and to secrete cytokines. Our aim is to understand the distribution and function of DCs in anatomical compartments affected directly or indirectly by the inflammation and how the DC phenotype relates to the clinical picture to be able to identify patients at risk to develop severe disease and start early treatment.
Methods currently used
We process a variety of tissue samples from human subjects (healthy controls and patients)- blood, tonsils, nasopharyngeal aspirates, bronchoalveolar lavage, bronchial wash, endobronchial biopsies, lymph node and lung tissue.
Techniques: Primary cell tissue culture, cell isolation and differentiation, in vitro DC stimulation, DC-T cell assays, multi-parametric flow cytometry, cell sorting, virus propagation and in vitro infection, confocal microscopy, immunohistochemistry, STED microscopy, ELISA, Luminex, quantitative RT-PCR, Western blot, ELISPOT analysis, tSNE analysis, RNASeq.
Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways.
PLoS Pathog. 2017 Jun;13(6):e1006462
Visualization of early influenza A virus trafficking in human dendritic cells using STED microscopy.
PLoS ONE 2017 ;12(6):e0177920
Human Lung Mononuclear Phagocytes in Health and Disease.
Front Immunol 2017 ;8():499
Dynamic Changes in Resident and Infiltrating Epidermal Dendritic Cells in Active and Resolved Psoriasis.
J. Invest. Dermatol. 2017 Apr;137(4):865-873
Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype.
Eur. Respir. J. 2016 08;48(2):484-94
Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans.
J. Immunol. 2016 06;196(11):4498-509
Protection of human myeloid dendritic cell subsets against influenza A virus infection is differentially regulated upon TLR stimulation.
J. Immunol. 2015 May;194(9):4422-30
Antigen delivery to early endosomes eliminates the superiority of human blood BDCA3+ dendritic cells at cross presentation.
J. Exp. Med. 2013 May;210(5):1049-63
Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells.
PLoS Pathog. 2012 ;8(3):e1002572
We gratefully receive financial support for our research from several organizations, currently from:
Swedish Research Council, Vetenskapsrådet
Karolinska Institutet (KID medel och senior forskartjänst)
Open positions and thesis projects
We are always looking for exceptional researchers and students to join our research group. In the spring semester, we are also looking for medical or Masters students who undertake a research project (Semester 8) to work on our ongoing study on Influenza virus infections in patients. Please contact the group leader:
Anna Smed Sörensen.