Heterozygous interferon signaling deficient mice as animal models for Chikungunya virus infection in the heart.

Although chikungunya virus (CHIKV)-caused cardiovascular diseases are frequently reported in clinics, the underlying mechanisms are poorly understood, which is primarily due to a lack of animal models. In this study, we report that CHIKV infection in homozygous interferon α/β receptor-deficient (ifnar1(-/-)) and interferon α/β/γ receptor-deficient (ifnag(-/-)) mice resulted in high viral loads in the hearts as early as day (D) 1 post-infection (p.i.) but with 100% mortality within three days p.i. In contrast, the heterozygous ifnar1(+/-)and ifnag(+/-) mice survived CHIKV infection and bore higher viral burdens in the heart tissues than the wild-type (WT) controls. Immunohistochemistry and flow cytometry revealed that more leukocytes, particularly neutrophils, infiltrated the heart of ifnag(+/-) and ifnar1(+/-) mice than WT mice. In addition, the Hematoxylin and Eosin staining analysis showed that CHIKV infection caused vasculitis in the left ventricles on D5 p.i. in both heterozygous groups and the vacuole formation and pyknosis in ifnar1(+/-) mice. Moreover, CHIKV infection may also lead to cardiac fibrosis, as indicated by the upregulation of the expression of the Connective Tissue Growth Factor gene in the hearts of ifnar1(+/-) mice. In summary, our data suggest that the heterozygous ifnar1(+/-) and ifnag(+/-) mice are invaluable for studying pathogenesis and testing therapeutic interventions for CHIKV-caused cardiac diseases.