Genetic determinants of susceptibility to coxsackievirus B1-induced chronic inflammatory myopathy: Effects of host background and major histocompatibility complex genes

Abstract

Infection of outbred CD-1 mice with the Tucson strain of coxsackievirus B1 (CVB1 T) leads to the development of chronic hind limb weakness and associated inflammatory muscle disease. Host factors that influence susceptibility have not been studied in this mouse model of chronic inflammatory myopathy (IM). Therefore, the pathogenesis was examined by using different inbred strains of mice. Initially, seven strains of mice with either the H-2 d or H-2 b major histocompatibility complex (MHC) haplotype were evaluated. All strains showed similar levels of acute mortality caused by viral infection, but chronic weakness or inflammation did not develop in two strains with the B6 background, regardless of their MHC haplotype. In susceptible mice, weakness was more likely to develop in the H-2 d strains than in mice with the H-2 b haplotype. Based on these results, H-2 congenic strains of the susceptible B10 background (C57BL/10 and B10.D2) and the resistant B6 background (C57BL/6 and B6.C-H2 d) were examined in greater detail. During acute infection, the kinetics and degree of viral replication in hind limb muscle were similar among B6 and B10 strains. By 4 weeks after infection, more intense chronic muscle inflammation and pathology were observed in susceptible B10 mice of the H-2 d haplotype than in those of the H-2 b haplotype. Resistant B6 mice did not show signs of inflammation or calcification, but they did exhibit some myopathic features, including centralized nuclei and variations in myofiber size and shape. These changes were less common in resistant B6 mice than in B10 strains but were significant when compared with changes in uninfected controls. Viral RNA persistence and elevated titers of antiviral IgG were more prevalent in but not restricted to susceptible strains. These studies demonstrate that host background genes confer resistance to chronic IM but also that MHC genes influence disease severity. They also reveal that susceptibility to acute CVB1 T infection is under different genetic control than that which mediates development of chronic post-viral IM.