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 1641 or +46 (0)8 517 76829
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.
|Saskia Thomas||PhD, postdoctoral fellow|
+46 (0)8 517 76698
Saskia did her undergraduate studies in Biochemistry at the Free University of Berlin and received her Ph.D. in Immunology 2012 from Charité Berlin. She joined our group as a postdoctoral fellow in 2012, and is the recipient of postdoctoral scholarships from Svenska Läkaresällskapet and Tore Nilssons stiftelse för medicinsk forskning.
|Faezzah Baharom||PhD student|
+46 (0)8 517 76698
Faezzah graduated with a B.Sc. (First class honours) in Biological Sciences at Nanyang Technological University, Singapore in 2011. Faezzah was selected for a KID PhD funded position to pursue doctoral studies and has been a PhD student in our group since 2012.
|Sindhu Vangeti||PhD student|
+46 (0)8 517 76698
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 76698
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.
Elisa Martini, PhD student (main supervisor: Liv Eidsmo).
Kimia Maleki, PhD student (main supervisor: Jonas Klingström)
Jens Gertow, PhD. 2013-2015.
Susanna Bächle, PhD. 2010-2015. (main supervisor: Markus Moll).
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.
Karolinska Institutet, Sweden
Drs. Hans-Gustaf Ljunggren, Jonas Klingström
Johan Grunewald, Anders Eklund, Karin Loré and Liv Eidsmo.
Karolinska University Hospital, Sweden
Dr. Danielle Friberg.
Umeå universitet, Sweden
Drs. Clas Ahlm and Anders Blomberg.
Dr. Alexander Ahlberg
Genentech, Inc, USA
Drs. Ira Mellman and Cécile Chalouni.
Dendritic cells in the respiratory system of healthy individuals
We have a good understanding of which DC subsets circulate in human blood. However, whether the same DC subsets are also found in other, less accessible tissues such as human airways and lung 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. In addition, we are investigating the function and composition of human DCs during IAV infection in vivo using nasal wash (nasopharynx) samples from suspected cases of IAV infection. Nasal wash samples are routinely collected to diagnose respiratory virus infection using PCR. This procedure is well tolerated and can be performed several times in the same individual, allowing for longitudinal studies of DCs and other immune cells present both during the course of and after clearance 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|
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 know 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 analyze 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.
Dendritic cells and regulation of immunity in sarcoidosis patients.
Sarcoidosis is a multisystem disorder that is thought to be an overreaction of the immune system, either to self-antigens or to microbial/environmental antigens. Since the lungs and airways are affected in the vast majority of all sarcoidosis patients, bronchoscopy is recommended to collect endobronchial biopsies for diagnosis. The role of DCs in sarcoidosis is only starting to unfold. It is well established that T cells are involved in the inflammation seen in sarcoidosis. The inflammation is antigen-driven (although the antigen is not defined) and 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 end organ 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. In this project we study DCs found in endobronchial biopsies, BAL 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.
Methods currently used
Primary cell tissue culture, cell isolation and differentiation, patient samples, virus propagation and infection, flow cytometry and cell sorting, confocal microscopy, ELISA, Luminex, quantitative RT-PCR, Western blot.
Expanded lung T-bet+RORγT+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype.
Eur. Respir. J. 2016 Aug;48(2):484-94
Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans.
J. Immunol. 2016 Jun;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
Dendritic cells at the interface of innate and adaptive immunity to HIV-1.
Curr Opin HIV AIDS 2011 Sep;6(5):405-10
IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via FcgammaRIIa.
Blood 2008 May;111(10):5037-46
Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells.
J. Virol. 2005 Jul;79(14):8861-9
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 interested to get in touch with talented potential co-workers. If you are interested in doing research within our group, as a post doc, PhD student or degree project student, please contact the group leader Anna Smed Sörensen.