Immune response to a conserved enteroviral epitope of the major capsid VP1 protein is associated with lower risk of cardiovascular disease
Nadežda Pupina,
Annela Avarlaid,
Helle Sadam,
Arno Pihlak,
Mariliis Jaago,
Jürgen Tuvikene,
Annika Rähni,
Anu Planken,
Margus Planken,
Eija Kalso,
Pentti J. Tienari,
Janne K. Nieminen,
Mikko R.J. Seppänen,
Antti Vaheri,
Dan Lindholm,
Juha Sinisalo,
Pirkko Pussinen,
Tõnis Timmusk,
Kaia Palm
Affiliations
Nadežda Pupina
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia
Annela Avarlaid
Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Helle Sadam
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Arno Pihlak
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia
Mariliis Jaago
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Jürgen Tuvikene
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Annika Rähni
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Anu Planken
The North Estonia Medical Center, Tallinn, Estonia
Margus Planken
The North Estonia Medical Center, Tallinn, Estonia
Eija Kalso
Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and Department of Pharmacology and SleepWell Research Programme, University of Helsinki, Finland
Pentti J. Tienari
Department of Neurology, Neurocenter, Helsinki University Hospital, and Translational Immunology Research Program, University of Helsinki, Finland
Janne K. Nieminen
Department of Neurology, Neurocenter, Helsinki University Hospital, and Translational Immunology Research Program, University of Helsinki, Finland
Mikko R.J. Seppänen
Department of Neurology, Neurocenter, Helsinki University Hospital, and Translational Immunology Research Program, University of Helsinki, Finland
Antti Vaheri
Department of Virology, Medicum, University of Helsinki, Finland
Dan Lindholm
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
Juha Sinisalo
Heart and Lung Center, Helsinki University Hospital, University of Helsinki, Finland
Pirkko Pussinen
Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Finland
Tõnis Timmusk
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
Kaia Palm
Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia; Corresponding author at: Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia.
Summary: Background: Major cardiac events including myocardial infarction (MI) are associated with viral infections. However, how specific infections contribute to the cardiovascular insults has remained largely unclear. Methods: We employed next generation phage display mimotope-variation analysis (MVA) to explore the link between antibody-based immune response and severe cardiovascular conditions. Here, we used a case-control design, including the first-stage discovery cohort (n = 100), along with cohorts for second-stage discovery (n = 329) and validation (n = 466). Findings: We observed strong antibody response to the peptide antigens with Gly-Ile-X-Asp (G-I-X-D) core structure in healthy individuals but not in patients with MI. Analysis of the origin of this epitope linked it with the N-terminus of the VP1 protein of poliovirus 3 (PV3), but also other species of picornaviruses. Consistently, we found low levels of antibody response to the G-I-X-D epitope in individuals with severe cardiac disease complications. Interpretation: Our findings imply that antibody response to the G-I-X-D epitope is associated with polio vaccinations and that high antibody levels to this epitope could discriminate healthy individuals from prospective MI patients as a blood-derived biomarker. Together, these findings highlight the importance of epitope-specific antibody response and suggest that protective immunity against the polio- and non-polio enteroviral infections support improved cardiovascular health. Funding: Estonian Ministry of Education (5.1-4/20/170), Estonian Research Council (PRG573, PRG805), H2020-MSCA-RISE-2016 (EU734791), H2020 PANBioRA (EU760921), European Union through the European Regional Development Fund (Project no. 2014-2020.4.01.15-0012), Helsinki University Hospital grants, Mary and Georg C. Ehrnrooth Foundation, Finnish Eye Foundation, Finska Läkaresällskapet, The Finnish Society of Sciences and Letters, Magnus Ehrnrooth Foundation and Sigrid Jusélius Foundation.
