CERIC
CECILIA SÖDERBERG-NAUCLER

Cecilia

Professor of Microbial Pathogenesis
Department of Medicine
Center for Molecular Medicine, L8:03
Karolinska Institutet at Karolinska Hospital

Laboratory Homepage

Cecilia.Naucler@ki.se

Tel: 08-517 79896

Group Members

Post-doctoral fellows:
Jenny Odeberg, PhD
Piotr Religa. MD,PhD
Afsar Rahbar, PhD
Stefania Varani, MD,PhD

Graduate students:
Mohammed Homman
Klas Strååt
Nina Wolmer Solberg
Madeleine Frederich
Monika Grudzinska, MD
Mensur Dzabic
Soley Omarsdottir, MD

Technical personnel:
Charlotte Tammik, medical technologist

Graduate students not yet registered:
Xingling Xu, MD, PhD student
Frida Herrgård, MD, PhD student
Chato Taher, MD

Independent senior investigator:
Rickard Glas, MD, PhD
Hong Qui, PhD
Rainer de Klark MSc
Giulio Preta, PhD

Recent evidence suggests that a previously unnoticed cytomegalovirus (CMV) infection can be detected in tissue specimens from patients with many inflammatory diseases such as cardiovascular diseases, autoimmune diseases as well as certain cancers. CMV infects and is carried by 70-100% of the world’s population. For many years, CMV was not considered to be a major human pathogen, since the virus only caused rare cases of CMV inclusion disease in neonates. CMV is an important pathogen in immunosuppressed patients such as transplant patients and AIDS patients. CMV disease in these groups of patients has also high-lightened the role of the virus in the development of other inflammatory diseases.

CMV can produce over 250 proteins, of which approximately 50 are essential for virus replication. Thus, the vast majority of the viral proteins are devoted to control important cellular and immunological functions that will assist the virus to co-exist with its host. We can now detect an active CMV infection in the vast majority of patients with different rheumatic diseases. Thus, 200 CMV encoded proteins will be present in tissues and may for example aggravate inflammation and control vascular changes and fibrosis development.  In support of this hypothesis, we have demonstrated that a CMV protein, US28 induces smooth muscle cell migration with relevance for vascular diseases development, that CMV induces LTB4 production in smooth muscle cells and that infection controls MMP/TIMP functions in macrophages; both with relevance for inflammation and fibrosis development. This project is focused on understanding how CMV through its unique ability to control host cell functions can contribute to the pathogenesis of inflammatory diseases. Our project includes two separate projects. The long-term goals of these projects are:

  • To further understand how CMV is involved in the development of inflammatory diseases.
  • To further understand the role of CMV as a link between  rheumatic diseases and cardiovascular diseases.

Research interactions with CERIC

Determine the prevalence of an active CMV infection in patients with different autoimmune diseases and cardiovascular diseases. –Is reactivation of CMV a risk factor for the development of cardiovascular diseases?

Further investigate how CMV induces and maintain inflammation; these studies include focus on 5-LO, cox-2, PGES pathways as well as the viral control of immunomodulatory cytokines such as IL-10 and TGF-b.

Examine whether CMV affect the production and biological activity of LL37.

Further determine the relevance of CD28 negative T cells in autoimmunity, CMV infection and cardiovascular disease.


Publications (2008-2013)

Qiu, H. ¤, Strååt, K. ¤, Rhabar A., Wan, M., Söderberg-Nauclér, C.¶, Jesper Z. Haeggström, J.¶ Human Cytomegalovirus Infection Induces 5-lipoxygenase Expression and Leukotriene B4 Production in Vascular Smooth Muscle Cells ¤ These authors contributed equally to this work and share first co-authorship.¶ Shared senior authorship. J Exp Med. 2008 Jan 21;205(1):19-24.

Straat, K., de Klark, R. Gredmark, S., Eriksson, P. and Soderberg-Naucler, C. CMV downreglates MMP-9 and upregulates TIMP-1 in infected macrophages. J Virol. 2009 Jan;83(2):830-5.

Cederarv, M., Soderberg-Naucler, C. ¶, and Odeberg, C. ¶, Human cytomegalovirus infection of plasmacytoid dendritic cells controls NK cell activation. Immunobiology. 2009;214(5):331-41. ¶ Shared senior authorship.

Religa P, Grudzinska MK, Bojakowski K, Soin J, Nozynski J, Zakliczynski M, Gaciong Z, Zembala M, Söderberg-Nauclér C. Host-derived smooth muscle cells accumulate in cardiac allografts: role of inflammation and monocyte chemoattractant protein 1. PLoS ONE. 2009;4(1):e4187.

Gredmark-Russ S, Dzabic M, Rahbar A, Wanhainen A, Björck M, Larsson E, Michel JB, Söderberg-Nauclér C. Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic anerysm. J Mol Med. 2009 Apr;87(4):347-56. Dec 16.

Strååt K, Liu C, Rahbar A, Zhu Q, Liu L, Wolmer-Solberg N, Lou F, Liu Z, Shen J, Jia J, Kyo S, Björkholm M, Sjöberg J, Söderberg-Nauclér C, Xu D Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst. 2009 Apr 1;101(7):488-97.

Varani, S., Mastroianni, A., Frascaroli, G., Tammik, C., Rahbar, A., Christensson, M., Rossini, G., Landini, M-P., and Soderberg-Naucler, C. Generalized Wegner´s granulomatosis in an immunocompetent adult after cytomegalovirus mononucleosis and bacterial urinary tract infection. Arthritis Rheum. 2009 May;60(5):1558-62.

Fasth AE, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, Nennesmo I, Malmberg KJ, Söderberg-Nauclér C, Trollmo C, Lundberg IE, Malmström V. T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells. J Immunol. 2009 Oct 1;183(7):4792-9. 14.

One of 45 group members of the Transplantation Society International CMV consensus group who wrote the International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A; Transplantation Society International CMV Consensus Group. Transplantation. 2010 Apr 15;89(7):779-95.

Giusti P, Frascaroli G, Tammik C, Gredmark-Russ S, Söderberg-Nauclér C, Varani S. The novel anti-rheumatic compound Rabeximod impairs differentiation and function of human pro-inflammatory dendritic cells and macrophages. Immunobiology. 2010 Apr 28.

Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A, Lira SA, Söderberg-Nauclér C, Smit MJ. HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal. 2010 Aug 3;3(133):ra58.

Grudzinska MK, Bojakowski K, Soin J, Stassen F, Söderberg-Nauclér C, Religa P. RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima. Herpesviridae. 2010 Dec 23;1(1):7.

Marashi SM, Raeiszadeh M, Workman S, Rahbar A, Soderberg-Naucler C, Klenerman P, Chee R, Webster AD, Milne RS, Emery VC. Inflammation in common variable immunodeficiency is associated with a distinct CD8(+) response to cytomegalovirus. J Allergy Clin Immunol. 2011 Jun;127(6):1385-93.

Baryawno, N., Rahbar. A., Odeberg, J., Wolmer-Solberg, N., Darabi, A., Khan, Z. , Taher, C., Sveinbjörnsson, B., Fuskevåg, O.-M., Segerström, L., Nordenskjöld, M., Siesjö, P., Kogner, P. , Johnsen, J-I. Söderberg-Nauclér, C. Detection of human cytomegalovirus in medulloblastomas reveals a novel therapeutic target. J Clin Invest. 2011 121(10):4043-55.

Dzabic,D., Rahbar, A., Yaiw, K-C., Naghibi, M., Religa, P. Fellström, B., Larsson, L. and Söderberg-Nauclér, C. Intragraft Cytomegalovirus Protein Expression Is Associated with Reduced Renal Allograft Survival. Clin Infect Dis. 2011 Nov;53(10):969-76.

Dzabic M, Bojakowski K, Kurzejamska E, Styczynski G, Andziak P, Söderberg-Nauclér C, Religa P. Sinificance of cytomegalovirus infection in the failure of native arteriovenous fistula. Clin Microbiol Infect. 2012 Jan;18(1):E5-7. doi: 10.1111/j.1469-0691.2011.03691.

Varani S, Rossini G, Mastroianni A, Tammik C, Frascaroli G, Landini MP, Castellani G, Söderberg-Nauclér C. High TNF-alpha and IL-8 levels predict low blood dendritic cell counts in primary cytomegalovirus infection. J Clin Virol. 2012 Jan 16.

Esteki-Zadeh, A., Karimi1,M., Strååt, K., Ammerpohl, O., Zeitelhofer, M., Jagodic, M., Mehrab-Mohseni, M., Sjöholm, L.,  Rahbar, A., Söderberg-Nauclér, C.¶. and Ekström, T. J. Human cytomegalovirus infection is sensitive to the host cell DNA methylation state, and alters global DNA methylation capacity. ¶ .¶ Shared senior authorshipEpigenetics. 2012 Jun 1;7(6):585-93.

Rahbar, A., Stragliotto, G. Dzabic, M., Peredo, I., Orrego,A., Willens, J. and Söderberg-Naucler, C. Low levels of Human Cytomegalovirus Infection in Glioblastoma Multiforme associates with high patient survival; -a case control study. Herpesviridae. 2012 Mar 16;3:3.

Bojakowski, K., Dzabic, M., Kurzejamska, E., Styczynski, G., Andziak, Gaciong, Z. Cecilia Söderberg-Nauclér, C. and Religa, P. A High Red Blood Cell Distribution Width Predicts Failure of Arteriovenous Fistula. PLoS One. 2012;7(5):e36482. 2012

Badrnya S, Butler LM, Söderberg-Naucler C, Volf I, Assinger A. Platelets directly enhance neutrophil transmigration in response to oxidised low-density lipoprotein. Thromb Haemost. 2012 Jul 26;108(4).

Xu, X.,Peter Bergman, P., Willows, T., Tammik, C., Sund, M., Hokfelt, T., Soderberg-Naucler # , C., Varani, S #  . BMC Neurol. 2012 Sep 4;12(1):87. #  shared senior authors

Bayer C, Varani S, Wang L, Walther P, Zhou S, Straschewski S, Bachem M, Söderberg-Naucler C#  , Mertens T#  , Frascaroli G#  . Human Cytomegalovirus (HCMV) Infection of M1- and M2- Macrophages Promotes a Pro-Inflammatory Signature and Stimulates HCMV Specific T-cell Responses. J Virol. 2013 Jan;87(1):67-79. doi: 10.1128/JVI.01585-12. Epub 2012 Oct 10. #  shared senior authors

Ning Xu, Florian Meisgen, Lynn M. Butler, Gangwen Han3 , Xiao-Jing Wang‡, Cecilia Söderberg-Nauclér, Mona Ståhle, Andor Pivarcsi, Enikö Sonkoly  MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes J Immunol. 2012 Dec 10.

Rahbar A, Orrego A, Peredo I, Dzabic M, Wolmer-Solberg N, Strååt K, Stragliotto G, Söderberg-Nauclér C. Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol. 2013 Feb 4. doi:pii: S1386-6532(12)00472-6. 10.1016/j.jcv.2012.12.018.

Stragliotto G, Rahbar A, Solberg NW, Lilja A, Taher C, Orrego A, Bjurman B, Tammik C, Skarman P, Peredo I, Söderberg-Nauclér C. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomised, double-blind, hypothesis-generating study. Int J Cancer. 2013 Feb 13. doi: 10.1002/ijc.28111.

Taher C, de Boniface J, Mohammad AA, Religa P, Hartman J, Yaiw KC, Frisell J, Rahbar A, Söderberg-Naucler C. High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes.  PLoS One. 2013;8(2):e56795. doi: 10.1371/journal.pone.0056795. 2013

Fornara O, Odeberg J, Khan Z, Stragliotto G, Peredo I, Butler L, Söderberg-Nauclér C. Human cytomegalovirus particles directly suppress CD4 T-lymphocyte activation and proliferation. Immunobiology. 2013 Jan 16. doi:pii: S0171-2985(13)00007-7. 10.1016/j.imbio.2013.01.002.

Jeffery HC, Söderberg-Naucler C, Butler LM. Human cytomegalovirus induces a biphasic inflammatory response in primary endothelial cells. J Virol. 2013 Mar 27.

Grudzinska MK, Kurzejamska E, Bojakowski K, Soin J, Lehmann MH, Reinecke H, Murry CE, Soderberg-Naucler C, Religa P.Monocyte chemoattractant protein 1-mediated migration of mesenchymal stem cells is a source of intimal hyperplasia. Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1271-9. Epub 2013 Apr 18.

Leepiyasakulchai C, Taher C, Chuquimia OD, Mazurek J, Söderberg-Naucler C, Fernández C, Sköld M. Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103(+) Lung Dendritic Cells during Pulmonary Tuberculosis. PLoS One. 2013 Jul 8;8(7):e69287. doi: 10.1371/journal.pone.0069287. Print 2013.

Shabir S, Kaul B, Pachnio A, Banham GD, Smith H, Chand S, Jham S, Harper L, Ball S, Rahbar A, Söderberg-Nauclér C, Moss P, Borrows R. Impaired Direct Priming of CD8 T Cells by Donor-Derived Cytomegalovirus Following Kidney Transplantation. J Am Soc Nephrol. 2013 Jul 11.

Wolmer-Solberg N, Baryawno N, Rahbar A, Fuchs D, Odeberg J, Taher C, Wilhelmi V, Milosevic J, Mohammad AA, Martinsson T, Sveinbjörnsson B, Johnsen JI, Kogner P, Söderberg-Nauclér C. Frequent detection of human cytomegalovirus in neuroblastoma: A novel therapeutic target? Int J Cancer. 2013 May 10. doi: 10.1002/ijc.28265.

Zahidul Khan, Koon-Chu Yaiw, Afsar Rahbar and Cecilia Söderberg-Nauclér.  Human cytomegalovirus (HCMV) immediate-early proteins degrade Connexin43 and disrupt gap junction communication; implications for a role in gliomagenesis. in press Carcinogenesis.

Söderberg Nauclér, C. Rahbar, A. and Stragliotto, G. High survival among glioblastoma patients receiving antiviral therapy against cytomegalovirus. in press The New England Journal of Medicine.

Reviews (2008-2013)

Soderberg-Naucler, C. 2008  HCMV microinfections in inflammatory diseases and cancer. J Clin Virol. Mar;41(3):218-23. Epub 2007 Dec 27.

Soderberg-Naucler, C, Dzabic, M and Rahbar, A. 2008. Understanding the molecular mechanisms involved in indirect effects of cytomegalovirus “Trends in Transplantation, Vol. II, nº 1-08”

Soderberg-Naucler, C, 2008.  Indirect effects of CMV. European Haematology Vol 2 Issue 1,

Varani S, Frascaroli G, Landini MP, Söderberg-Nauclér C. Human cytomegalovirus targets different subsets of antigen-presenting cells with pathological consequences for host immunity: implications for immunosuppression, chronic inflammation and autoimmunity. Rev Med Virol. 2009 May;19(3):131-45.

Varani, S. Landini, MP and Söderberg-Nauclér, C. Cytomegalovirus-induced autoimmunity. Autoimmune Disorders: Symptoms, Diagnosis and Treatment. Nova Publishers  2010.

Mensur Dzabic and Cecilia Söderberg-Nauclér Indirect effects of cytomegalovirus: a challenge for improved long-term outcome in transplant recipients.  Br Transplant Journal, Suppl. Febr. 2011.

Johnsen, JI, Baryawno, N and Söderberg-Nauclér, C. Is human cytomegalovirus a target in cancer therapy? Oncotarget. 2011 Dec;2(12):1329-38.

Söderberg-Nauclér C, Johnsen JI. Cytomegalovirus infection in brain tumors: A potential new target for therapy? Oncoimmunology. 2012 Aug 1;1(5):739-740.

Gredmark-Russ S. and Söderberg-Nauclér, C. Dendritic cell biology in cytomegalovirus infection, Virulence. 2012 Oct 17;3(7).
 

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