Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

Abstract

The pathogenesis of viral myocarditis is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a model of infection with coxsackievirus B3 (CVB3) to characterize the contribution of host genetics to viral myocarditis in mice of different genetic backgrounds but with a common H2 haplotype: A/J and B10.A-H2 a .Here we have used Evans blue dye as a quantitative biomarker for susceptibility to CVB3-induced myocarditis in addition to histopathological semiquantitative measures. We have found evidence of linkage between susceptibility to viral myocarditis and three loci. A locus on chromosome 1 centered on D1Mit200 was linked to sarcolemmal disruption in males (P ¼ 0.00005), a second locus on chromosome 4 centered on D4Mit81 was also linked to sarcolemmal disruption in males (P ¼ 0.0022). A third locus on distal chromosome 3 centered on D3Mit19 was linked to myocardial infiltration, with a logarithm of odds (LOD) score of 4.7 (P ¼ 0.0045), as well as sarcolemmal disruption in females (P ¼ 0.0015). These results provide strong evidence for the presence of loci contributing to the susceptibility of mice to viral myocarditis.

Genetic Differences in Bone Marrow-Derived Lymphoid Lineages Control Susceptibility to Experimental Autoimmune Myocarditis

“…MHC molecules modulate adaptive immune responses, including autoimmune responses, via their unique role in Ag presentation. Yet, at least seven non-MHC loci have been reported to influence susceptibility to viral or immunization-induced autoimmune myocarditis in mouse (18,35,36). Linkage of these loci to apoptosis or tolerance induction was suggested; however, the mechanisms by which they modulate disease susceptibility remain to be investigated.…”

Quantitative Trait Locus Analysis, Pathway Analysis, and Consomic Mapping Show Genetic Variants of Tnni3k, Fpgt, or H28 Control Susceptibility to Viral Myocarditis

“…Strong linkage of chromosome 3 to myocarditis, sarcolemmal disruption (16), and viral titer (Supplemental Fig. 2) encouraged us to isolate the role of chromosome 3 in viral myocarditis.…”

“…The mice were maintained in the McGill University animal facility in compliance with the Canada Council on Animal Care as approved by the McGill University Animal Care Committee. Coxsackievirus B3 used for time-course and microarray experiments was the CVB3-CG strain, as used previously (16). All other experiments including CSS3/B6/F1 as well as [CSS3 3 B6]F 2 were infected with the plaque purified CVB3-H3 (18), generously provided as a plasmid by the laboratory of Dr. Kirk Knowlton (University of California, San Diego, San Diego, CA).…”

“…Previously, using an F 2 cross between susceptible A/J and resistant B10.A-H2 a (B10.A) mice, we identified three QTL on chromosomes 1 (viral myocarditis susceptibility 2 [Vms2]), 3 (Vms1), and 4 (Vms3). Only Vms1 was linked to the three phenotypes under study [i.e., myocarditis score (p = 0.005), extent of sarcolemmal damage (p = 0.001) (16), and heart viral load (p = 0.010)]. This suggested that Vms1 is a central determinant of disease severity; in the current study, we seek to determine the precise contribution of Vms1 in viral myocarditis.…”

Extending Human Induced Pluripotent Stem Cell Technology to Infectious Diseases

“…It is well known that the susceptibility to viral myocarditis is genetically determined. 13 The progression of viral myocarditis to dilated cardiomyopathy may be also influenced by genetic susceptibility factors.14 By deriving iPSCs not only from healthy individuals but also from patients affected by viral myocarditis (assuming their susceptibility to the disease) and from patients who have developed dilated cardiomyopathy after viral myocarditis, it might be possible to elucidate the molecular mechanisms of this susceptibility further. Knowledge of the signal transduction pathways that confer resistance to virus-mediated myocardial damage might inform the development of specific drugs to prevent the potentially devastating consequences of this disease.…”