Attenuated strain of CVB3 with a mutation in the CAR-interacting region protects against both myocarditis and pancreatitis

Ninaad Lasrado,Arunakumar Gangaplara,Shi-Hua Xiang,Chandirasegaran Massilamany,Rajkumar Arumugam,Asit K Pattnaik,Rakesh H Basavalingappa,Allison Shelbourn,Jay Reddy,Mahima T Rasquinha,David Steffen,Gustavo Delhon

doi:10.1038/s41598-021-90434-w

Abstract

Coxsackievirus B3 (CVB3), is commonly implicated in myocarditis, which can lead to dilated cardiomyopathy, in addition to causing acute pancreatitis and meningitis. Yet, no vaccines are currently available to prevent this infection. Here, we describe the derivation of a live attenuated vaccine virus, termed mutant (Mt) 10, encoding a single amino acid substitution H790A within the viral protein 1, that prevents CVB3 infection in mice and protects from both myocarditis and pancreatitis in challenge studies. We noted that animals vaccinated with Mt 10 developed virus-neutralizing antibodies, predominantly containing IgG2a and IgG2b, and to a lesser extent IgG3 and IgG1. Furthermore, by using major histocompatibility complex class II dextramers and tetramers, we demonstrated that Mt 10 induces antigen-specific T cell responses that preferentially produce interferon-γ. Finally, neither vaccine recipients nor those challenged with the wild-type virus revealed evidence of autoimmunity or cardiac injury as determined by T cell response to cardiac myosin and measurement of circulating cardiac troponin I levels, respectively. Together, our data suggest that Mt 10 is a vaccine candidate that prevents CVB3 infection through the induction of neutralizing antibodies and antigen-specific T cell responses, the two critical components needed for complete protection against virus infections in vaccine studies.

Highlights

Part of the Biochemistry, Biophysics, and Structural Biology Commons, Cell and Developmental Biology Commons, Immunology and Infectious Disease Commons, Medical Sciences Commons, Veterinary Microbiology and Immunobiology Commons, and the Veterinary Pathology and Pathobiology Commons
By generating a full-length infectious clone of the Coxsackievirus B3 (CVB3) genome, we had previously reported that the pBRCVB3 virus induces mainly pancreatitis, but its myocarditis-inducing ability was severely impaired[11]
Using this virus as the backbone, we sought to create attenuated mutant viruses that would lose their ability to induce both myocarditis and pancreatitis, leading us to identify one mutant virus possessing a mutation in the coxsackievirus-adenovirus receptor (CAR)-binding region as a vaccine candidate in the prevention of CVB3 infection

Summary

Introduction

Part of the Biochemistry, Biophysics, and Structural Biology Commons, Cell and Developmental Biology Commons, Immunology and Infectious Disease Commons, Medical Sciences Commons, Veterinary Microbiology and Immunobiology Commons, and the Veterinary Pathology and Pathobiology Commons This Article is brought to you for free and open access by the Veterinary and Biomedical Sciences, Department of at DigitalCommons@University of Nebraska - Lincoln. We describe the derivation of a live attenuated vaccine virus, termed mutant (Mt) 10, encoding a single amino acid substitution H790A within the viral protein 1, that prevents CVB3 infection in mice and protects from both myocarditis and pancreatitis in challenge studies. Our data suggest that Mt 10 is a vaccine candidate that prevents CVB3 infection through the induction of neutralizing antibodies and antigen-specific T cell responses, the two critical components needed for complete protection against virus infections in vaccine studies

Methods

Results

Conclusion