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

doi:10.1016/j.ebiom.2022.103835

Immune response to a conserved enteroviral epitope of the major capsid VP1 protein is associated with lower risk of cardiovascular disease

EBioMedicine. 2022 Feb:76:103835. doi: 10.1016/j.ebiom.2022.103835. Epub 2022 Jan 25.

Authors

Nadežda Pupina¹, Annela Avarlaid², Helle Sadam³, Arno Pihlak¹, Mariliis Jaago³, Jürgen Tuvikene⁴, Annika Rähni³, Anu Planken⁵, Margus Planken⁵, Eija Kalso⁶, Pentti J Tienari⁷, Janne K Nieminen⁷, Mikko R J Seppänen⁷, Antti Vaheri⁸, Dan Lindholm⁹, Juha Sinisalo¹⁰, Pirkko Pussinen¹¹, Tõnis Timmusk³, Kaia Palm¹²

Affiliations

¹ Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia.
² Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia.
³ Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia.
⁴ Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia; dxlabs LLC, Mäealuse 4, Tallinn 12618, Estonia.
⁵ The North Estonia Medical Center, Tallinn, Estonia.
⁶ Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and Department of Pharmacology and SleepWell Research Programme, University of Helsinki, Finland.
⁷ Department of Neurology, Neurocenter, Helsinki University Hospital, and Translational Immunology Research Program, University of Helsinki, Finland.
⁸ Department of Virology, Medicum, University of Helsinki, Finland.
⁹ Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
¹⁰ Heart and Lung Center, Helsinki University Hospital, University of Helsinki, Finland.
¹¹ Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Finland.
¹² Protobios LLC, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia. Electronic address: kaia@protobios.com.

Abstract

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.

Keywords: Antibodies; Cardiovascular diseases; Enteroviruses; Epitope; Myocardial infarction; Poliovirus.

MeSH terms

Capsid
Capsid Proteins
Cardiovascular Diseases*
Epitopes
Humans
Immunity
Poliovirus*
Prospective Studies

Substances

Capsid Proteins
Epitopes