Receptor-mediated tropism and evolution of entero- and parechoviruses
Human entero- and parechoviruses belong to family Picornaviridae, which comprise more than 250 human-infecting pathogens. The known members of these species include poliovirus, rinovirus (the flu virus), enterovirus (the most common cause of aseptic meningitis) and human parechoviruses 1 and 3, which are common in severe infections of newborns. The conserved nature of picornaviruses, both at structural and sequence levels hamper diagnostics, and drug/vaccine development; development of which would greatly benefit health care systems and control of development of antibiotic resistance.
The project is interested in few entero- and parechoviruses, namely coxsackievirus A9 (CAV9) and human parechovirus 1 and 3 (HPEV1 and 3). The former two possess a specific RGD motif in C-terminus of VP1 capsid protein, through which these viruses are thought to bind to cell surface integrin receptors. The receptor for HPEV3 is currently unknown. The research is focused on structural aspects (cryoEM and molecular modeling), receptor tropism (receptor identification and function in virus infection), and cellular endocytosis (using confocal microscopy and virus- and cell marker-specific antibodies), which are reflected on sequence variations (evolution) in specified cases. The project is also interested in real-time imaging of picornavirus transmission, and is developing marker-tagged virus vectors for such purposes. Another aspect of interest is picornavirus diagnostics via RT-qPCR, microarray and immunoserology (e.g. synthetic antibody libraries).
Publications:
Seitsonen, J.J.T, Shakeel, S., Susi, P., Pandurangan, A.P., Sinkovits, R.S., Hyvönen, H., Laurinmäki, P., Ylä-Pelto, J., Topf, M., Hyypiä, T. & Butcher, S. 2012. Structural analysis of coxsackievirus A7 reveals changes associated with uncoating. Under revision (Journal of Virology).
McWilliam Leich, E.C., Cabrerizo, M., Cardosa, J., Harvala, H., Ivanova, O.E., Koike, S., Kroes, A.C.M., Lukashev, A., Perera, D., Roivainen, M., Susi, P., Trallero, G., Evans, D.J. & Simmonds, P. 2012. The association of recombination events in the founding and emergence of subgenogroup evolutionary lineages of human enterovirus 71. Journal of Virology. Journal of Virology. Accepted for publication.
Heikkilä, O., Kainulainen, M. & Susi, P. 2011. A combined method for rescue of modified enteroviruses by mutagenic primers, long PCR and T7 RNA polymerase-driven in vivo transcription. Journal of Virological Methods 171, 129-133.
Liljeroos L., Ora A., Huiskonen J.T., Susi P. & Butcher S.J. 2011. Electron cryotomography of Measles virus reveals that matrix protein coats the ribonucleocapsid within intact virions. Proceedings of National Academy of Sciences USA 108, 18085–18090.
Heikkilä, O., Susi, P., Tevaluoto, T., Härmä, H., Marjomäki, V., Hyypiä, T. & Kiljunen, S. 2010. Endocytosis of coxsackievirus A9 via integrin aVb6 and β2-microglobulin is mediated by dynamin and Arf6 but not caveolin1. Journal of Virology 84, 3666-3681.
McWilliam Leich, E.C., Cabrerizo, M., Cardosa, J., Harvala, H., Ivanova, O.E., Kroes, A.C.M., Lukashev, A., Muir, P., Odoom, J., Roivainen, M., Susi, P., Trallero, G., Evans, D.J. & Simmonds, P. 2010. Evolutionary dynamics and temporal/geographical correlates of recombination in the human enterovirus echoviruses 9, 11 and 30. Journal of Virology 84, 9292-9300.
Seitsonen, J.J.T, Susi, P., Heikkilä, O., Sinkovits, R., Laurinmäki, P., Hyypiä, T. & Butcher, S.J. 2010. Interaction of αVβ3 and αVβ6 integrins with human parechovirus 1. Journal of Virology 84, 8509-8519.
Heikkilä, O., Susi, P., Stanway, G. & Hyypiä, T. 2009. Integrin αVβ6 is a high-affinity receptor for coxsackievirus A9. Journal of General Virology 90, 197-204.
Susi, P., Hattara, L., Waris, M., Siitari, H., Hyypiä, T. & Saviranta, P. 2009. Typing of enteroviruses by use of microwell oligonucleotide arrays. Journal of Clinical Microbiology 47, 1863-1870.
Collaborators:
Prof. Sarah Butcher (Institute of Biotechnology, University of Helsinki)
Dos. Urpo Lamminmäki (Department of Biotechnology, University of Turku)
Dos. Matti Waris (Department of Virology, University of Turku)
Dr. Katja Wolthers (Amsterdam Medical Centre, Amsterdam, The Netherlands)
Prof. Peter Simmonds (University of Edinburgh, Edinburgh, Scotland)
Prof. J.-P. Himanen (Memorial Sloan-Kettering Cancer Center, New York, USA)