Mechanisms of activation of innate immunity in viral infections

​Ilkka Julkunen, M.D., Ph.D., Professor, Laura Kakkola, Ph.D., Senior scientist, Anya Kutsaya, M.Sc., Research scientist, Felix He, Med.student, Sari Maljanen, Lab. technician
E-mail ilkka.julkunen@; tel. +358-2-333 7460 or +358-40-352 2941

Viral infections in the host lead to the activation of innate and virus-specific adaptive immune responses. The structural components and the genetic material (viral RNA/DNA) of viruses activate innate immune responses via cell surface or intracellular pattern recognition receptors. In viral infections Toll-like (TLR), RIG-I-like (RLR) and NOD receptors (NLR) recognize foreign structures, which leads to the activation of intracellular signaling pathways including the inflammasome, MAP kinases pathways and IRF and NF-kB family transcription factors. In response to activation of these signaling pathways virus infected cells produce interferons (IFN), other cytokines and many innate immune molecules. In antigen-presenting cells (APC), in macrophages and dendritic cells (DCs), innate immune responses regulate cell activation and antigen presentation in APCs. Most pathogenic viruses express proteins that can interfere with the activation and functions of innate immune molecules. Our research project concentrates on analyzing how viral infections, viral proteins such as vaccines and viral genetic material trigger the activation of host innate immune responses and how they contribute to the activation of antigen presentation and adaptive immunity. In addition, we intend to identify novel mechanisms or means to prevent the replication of viruses and excessive inflammatory responses induced by virus infection.    

 Figure 1. Schematic representation of intracellular signaling pathways involved in the regulation of antiviral IFN gene expression.

The major goals of our research are related to the activation mechanisms of human macrophages and DCs in response to virus infection (influenza, Sendai, RSV), viral RNA or their structural components such as vaccines (influenza vaccines). We intend to identify molecular mechanisms regulating the activation of innate immune responses in human model cell systems. In addition, we will specifically analyze the activation of human DCs in response to influenza infection or viral antigen loading and identify virus-specific peptides by proteomics approaches that are presented by human DCs. We will also visualize these events by confocal and live microscopic imaging.

Virus infection usually triggers the production of antibody responses against the infecting virus which reflects the infection as well as it may produce long term protection against the virus tha was causing the disease. We will characterize by seroepidemiological means influenza and RSV disease burden in young children during their early childhood. By analyzing a large serum cohort collected from young children we will obtain a good view of influenza and RSV disease burden and the efficacy of childhood influenza vaccination. We will also clone and express various influenza and RSV genes in order to use these molecules for basic research purposes and as diagnostic reagents for microarray technology that are applicable for large scale seroepidemiological and diagnostic applications. We also take part in identifying the disease mechanisms that were involved in pandemic influenza vaccine induced narcolepsy in children and adolescent.

• Kutsaya A., Teros-Jaakkola T., Kakkola L., Toivonen L., Peltola V., Waris M., Julkunen I. Prospective clinical and serological follow-up in early childhood reveals a high rate of subclinical RSV infection and a relatively high reinfection rate within the first three years of life. Epid. Infect. In press, 2016
• Tynell J., Westenius V., Rönkkö E., Munster V.J., Melen K., Österlund P., Julkunen I. Middle East respiratory syndrome coronavirus (MERS-CoV) shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J. Gen Virol. In press. 2016.
• Mäkelä SM, Österlund P, Westenius V, Latvala S, Diamond MS, Gale M Jr, Julkunen I. RIG-I signaling is essential for influenza B virus-induced rapid interferon gene expression. J. Virol. 89, 12014-25, 2015.
• Ahmed S.S., Volkmuth W., Duca J., Corti L., Pallaoro M., Pezzicoli A., Karle A., Rigat F., Rappuoli R., Narasimhan V., Julkunen I., Vuorela A., Vaarala O., Nohynek H., Pasini F.L., Montomoli E., Trombetta C., Adams C.M., Rothbard J., Steinman L. Antibodies to influenza nucleoprotein cross-react with hypocretin receptor. Science Translat. Med. 7, 294ra105, 2015.
• Jiang M., Österlund M., Fagerlund R., Rios D.N., Hoffmann A., Poranen M.M., Bamford D.H. and Julkunen I. MAP kinase p38α regulates type III interferon (IFN-λ1) gene expression in human monocyte-derived dendritic cells in response to RNA stimulation. J. Leukoc. Biol. 97, 307-20, 2015.
• Ibsen MS, Gad HH, Andersen LL, Hornung V, Julkunen I, Sarkar SN, Hartmann R. Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling. Nucleic Acids Res. 43, 5236-48, 2015.
• Vaarala O., Vuorela A., Partinen M., Baumann M., Freitag T., Meri T., Saavalainen P., Jauhiainen M., Soliymani R., Kirjavainen T., Olsen P., Saarenpää-Heikkilä O., Rouvinen J.,  Roivainen M., Nohynek H., Jokinen J., Julkunen I. and Kilpi T. Antigenic differences between AS03 adjuvanted pandemic vaccines: implications for Pandemrix-associated narcolepsy risk. PLoS ONE 9, e114361, 2014.
• Westenius V., Mäkelä S.M., Ziegler T., Julkunen I. and Österlund P. Efficient replication and strong induction of innate immune responses by H9N2 avian influenza virus in human dendritic cells. Virology 471, 38–48, 2014.
• Julkunen I. and Partinen M. Disease mechanisms in narcolepsy remain elusive. Nat. Rev. Neurol. 10, 616-617, 2014.
• Arilahti V., Mäkelä S.M., Tynell J., Julkunen I. Österlund P. Novel Avian Influenza A (H7N9) Virus induces impaired interferon responses in Human Dendritic Cells. PLoS ONE, 9, e96350, 2014
• Bergman P., Adori C., Vas S., Kai-Larsen Y., Sarkanen T., Cederlund A., Agerberth B., Julkunen I., Horvath B., Kostyalik D., Kalmár L., Bagdy G., Huutoniemi A., Partinen M., Hökfelt T. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc. Natl. Acad. Sci. U S A. 111, E3735-3744, 2014.
• Syrjänen R.K., Jokinen J., Ziegler T., Sundman J., Lahdenkari M., Julkunen I., M. Kilpi T.M. The effectiveness of pandemic and seasonal influenza vaccines in preventing febrile laboratory-confirmed A(H1N1)pdm09 influenza virus infections in adults. PLoS ONE, 9, e108538, 2014.
• Partinen M., Kornum B.R., Plazzi G., Jennum P., Julkunen I., and Vaarala O. Narcolepsy as an autoimmune disease:  Relationships with H1N1 vaccinations and infection. Lancet Neurol. 13, 600-613, 2014.
• Melén K., Partinen M., Tynell J., Sillanpää M., Himanen S-L., Saarenpää-Heikkilä O., Hublin C., Olsen P., Ilonen J., Nohynek H., Syrjänen R., Kilpi T., Vuorela A., Kirjavainen T., Vaarala O. and Julkunen I. No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy After Pandemrix Vaccination Campaign in Finland. PLoS ONE, 8, e68402, 2013
• Kakkola L, Denisova OV, Tynell J, Viiliäinen J, Ysenbaert T, Matos RC, Nagaraj A, Ohman T, Kuivanen S, Paavilainen H, Feng L, Yadav B, Julkunen I, Vapalahti O, Hukkanen V, Stenman J, Aittokallio T, Verschuren EW, Ojala PM, Nyman T, Saelens X, Dzeyk K, and Kainov DE. Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice. Cell Death Dis. 4:e742, 2013.
• Nousiainen L., Sillanpää M., Jiang M., Thompson J., Taipale J. and Julkunen I. Human kinome analysis reveals novel kinases contributing to virus infection and RIG-I-induced type I and type III interferon gene expression. Innate Immun. 19, 516-530, 2013
• Österlund P., Strengell M., Sarin L.P., Poranen M.M., Fagerlund R., Melén K. and Julkunen I. Incoming influenza A virus evades early host recognition, while influenza B virus induces interferon expression directly upon entry. J. Virol. 86, 11183-11193, 2012.
• Jiang M., Österlund P., Sarin P., Poranen M.M., Bamford D.H., Guo D. and Julkunen I. Innate Immunity Responses in Human Monocyte-derived Dendritic Cells Are Highly Dependent on the Size and the 5’-Phosphorylation of RNA Molecules. J. Immunol. 187, 1713-1721, 2011.
• Strengell M., Ikonen N., Ziegler T., and Julkunen I. Minor changes in the hemagglutinin of influenza A(H1N1)2009 virus alter its antigenic properties. PLoS ONE, 6, e25848, 2011.

• Prof. Dennis Bamford ja dos. Minna Poranen, University of Helsinki
• Dos. Denis Kainov, FIMM University of Helsinki
• Prof. Olli Vapalahti, Prof. Kalle Saksela and Prof. Antti Vaheri, University of Helsinki
• Dos. Tuula Nyman, University of Helsinki
• Dos. Veijo Hukkanen, dos. Matti Waris, dos. Tytti Vuorinen, University of Turku
• Prof. Ville Peltola, TYKS and University of Turku
• Prof. Sirpa Jalkanen and Prof. Marko Salmi, University of Turku
• Dos. Anne Rokka and Dr. Susumu Imanishi, University of Turku
• Prof. Anne Pitkäranta, Helsinki University Central Hospital, Ear, nose and throath clinics
• Prof. Markku Partinen, VitalMed and University of Helsinki
• Dos. Sampsa Matikainen, Finnish Institute of Ocuupational Health
• Drs. Pamela Österlund, Krister Melen, Niina Ikonen, National Institute for Health and Welfare (THL), Helsinki

International collaboration
• Prof. Stephan Ludwig, University of Munster, Germany
• Dr. Thorsten Wolff, Robert-Koch Institute, Berlin, Germany
• Prof. Tomas Hökfelt and Prof. Jussi Taipale, Karolinska Institute
• Prof. John Hiscott, Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, FL, USA
• Prof. Michael Gale Jr. University of Washington, USA
• Prof. Antonio Lanzavecchia, Institute of Biomedicine, Bellinzona, Switzerland