ABSTRACT
Coxsackievirus B type 3 (CVB3) is one of the major causative pathogens associated with viral meningitis and myocarditis, which are widespread in the human population and especially prevalent in neonates and children. These infections can result in dilated cardiomyopathy (DCM) and other severe clinical complications. There are no vaccines or drugs approved for the prevention or therapy of CVB3-induced diseases. During screening for anti-CVB3 candidates in our previous studies, we found that jiadifenoic acids C exhibited strong antiviral activities against CVB3 as well as other strains of Coxsackie B viruses (CVBs). The present studies were carried out to evaluate the antiviral activities of jiadifenoic acids C. Results showed that jiadifenoic acids C could reduce CVB3 RNA and proteins synthesis in a dose-dependent manner. Jiadifenoic acids C also had a similar antiviral effect on the pleconaril-resistant variant of CVB3. We further examined the impact of jiadifenoic acids C on the synthesis of viral structural and non-structural proteins, finding that jiadifenoic acids C could reduce VP1 and 3D protein production. A time-course study with Vero cells showed that jiadifenoic acids C displayed significant antiviral activities at 0-6 h after CVB3 inoculation, indicating that jiadifenoic acids C functioned at an early step of CVB3 replication. However, jiadifenoic acids C had no prophylactic effect against CVB3. Taken together, we show that jiadifenoic acids C exhibit strong antiviral activities against all strains of CVB, including the pleconaril-resistant variant. Our study could provide a significant lead for anti-CVB3 drug development.
ABSTRACT
The structure of coxsackievirus and adenovirus receptor's CAR is similar to adhesion molecules. In the adult heart, the majority of CAR localizes at the intercalated disc. Germ line CAR deletion induces embryonic lethality at E11.5 with evidence of a cardiac abnormality. The CAR role as a viral receptor is well known; however, its precise function in the heart for enterovirus infection is not clear. To understand the role of CAR in the cardiac myocyte, we generated cardiac-specific CAR knockout mice using a CAR floxed allele and alpha-MHC-Mer CRE Mer mice. Western blot analysis and immunofluorescent stain of ventricles at 6 weeks after 2 weeks tamoxifen administration, CAR expression was significantly decreased in CAR(f/f) MCM mice but not in CAR(f/f) mice heart. Enterovirus was intraperitoneally infected into CAR(f/f) MCM and CAR(f/f) mice (n=10 each). CAR disruption was dramatically reduced virus infection and replication in the heart but not different in liver, spleen, and pancreas. Cardiac myocyte damage was significantly reduced in the CAR(f/f) MCM mutant mice by evans blue dye stain. In addition, the CAR(f/f) MCM mutant mice heart inflammation and fibrosis were decreased in H&E and trichrome stain compare to CAR(f/f) control mice. CAR expression was required for normal ventricular function, but it is the cause of enterovirus infection. In the adult mice heart, CAR deletion was significantly reduced viral infection, proliferation, and myocarditis. These results suggested that CAR deletion could be useful therapeutic strategy to prevent viral myocarditis.