Molecular determinants of disease in coxsackievirus B1 murine infection

Abstract

To understand better how different genomic regions may confer pathogenicity for the coxsackievirus B (CVB), two intratypic CVB1 variants and a number of recombinant viruses were studied. Sequencing analysis showed 23 nucleotide changes between the parental non-pathogenic CVB1N and the pathogenic CVB1Nm. Mutations present in CVB1Nm were more conserved than those in CVB1N when compared to other CVB sequences. Inoculation in C3H/HeJ mice showed that the P1 region is critical for pathogenicity in murine pancreas and heart. The molecular determinants of disease for these organs partially overlap. Several P1 region amino acid differences appear to be located in the decay accelerating factor (DAF) footprint CVBs. CVB1N and CVB1Nm interacted with human CAR, but only CVB1N seemed to interact with human DAF, as determined using soluble receptors in a plaque reduction assay. However, the murine homologue Daf-1 did not interact with any virus assessed by haemagglutination. The results of this study suggest that an unknown receptor interaction with the virus play an important role in the pathogenicity of CVB1Nm. Further in vivo studies may clarify this issue.

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells

“…The identification of a single CV-B6 amino acid that is most likely responsible for the lytic phenotype, more efficient progeny production and DAF-usage is in line with previous reports that have shown strong effects for single or few amino acid substitutions on the receptor usage, cell and tissue tropism and pathogenesis (Al-Hello et al, 2005Caggana et al, 1993;Chua et al, 2008;Cifuente et al, 2011;Gullberg et al, 2010;Halim and Ramsingh, 2000;Kim and Racaniello, 2007;Knowlton et al, 1996;Novoselov et al, 2012;Paananen et al, 2013;Pan et al, 2011;Pelletier et al, 1998;Polacek et al, 2005;Ramsingh and Collins, 1995;Ramsingh et al, 1997;Schmidtke et al, 2000). A phenomenon similar to our CV-B6 model has been described previously using CV-B2-Ohio strain that induces persistent non-cytolytic infection in CAR-deficient RD-cells.…”

The Crystal Structure of a Coxsackievirus B3-RD Variant and a Refined 9-Angstrom Cryo-Electron Microscopy Reconstruction of the Virus Complexed with Decay-Accelerating Factor (DAF) Provide a New Footprint of DAF on the Virus Surface

“…Virulence determinants have been described throughout the genome (19,20,30,51,65), including the P1 region, which encodes the structural proteins (7,10,13,25,48,49,56). The capsid surface presents a topology of structural motifs that largely dictate receptor recognition and usage, directly affecting tropism and pathogenicity.…”

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

“…Possibilities include the β2AR and AChR, which have been found to target the chronic phase of myocarditis (i.e., DCM) and might fit the profile of anti-idiotype autoantibodies [68–73]. However, several investigators have isolated at least five additional, as yet unidentified, proteins to which CVB3 binds that may also represent receptors [87, 88]. …”

“…Alternatively, the effects of these anti-idiotype antibodies on the course of myocarditis could be studied to determine whether they exacerbate or ameliorate disease symptoms. Finally, a dedicated search for anti-idiotype antibodies directed against CAR, DAF, the β2AR, AChR, and other novel CVB receptor candidates [87, 88] should be undertaken. The possibility that these receptor anti-idiotypes might correspond to anti-cardiac myosin autoAbs should also be considered [80, 81].…”

“…But there could be an alternative explanation for these findings. When CAR is not available for CV to use it could use other receptors [87, 88]. In our experience, when CAR is not used as a receptor viral replication in the heart is lower but inflammation is far more severe (80% vs. 10%) [12, 15].…”