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There were no differences in heart morphology and tissue composition. (I) Masson's trichrome staining of paraffin sections from hearts of 10-week-old wild-type (WT), chCAR transgenic (TG), and noncardiac CAR KO (ncKO) mice. (H) Heart-weight-to-body-weight ratio (HW/BW) was normal in transgenic and ncKO animals. (G) The chCAR transgene is exclusively expressed in the hearts of ncKO animals. (F) In wild-type tissues, mouse CAR mRNA is expressed at normal levels as determined by TaqMan analysis, while expression in noncardiac knockout mice (ncKO) is at the detection limit (Fc, fold change). (E) In transgenic animals, chicken CAR (chCAR) protein is expressed and localizes to the intercalated disc. Heterozygous offspring with (e) and without (f) the transgene were mated to obtain the noncardiac CAR KO animals (k). These animals were mated with heterozygote CAR-deficient mice carrying the recombined mouse CAR allele (CAR rec b). The transgenic mouse expresses chicken CAR (chCAR) under the control of the heart-specific MLC-2 promoter (a). Genotypes of animals (a to k) are provided below. (D) Pedigree of the heart-specific CAR rescue animals with the parental (P), F1, and F2 generations. Homozygous CAR knockout mice with the chCAR transgene (k) are available after two generations. The heterozygous knockout contains a recombined CAR allele with a residual lox side after excision of exon 1 (triangle b). Mouse CAR is expressed from the wild-type alleles. The MLC promoter drives expression of chCAR exclusively in the heart (a). Nuclei are stained in blue (4′,6-diamidino-2-phenylindole ). (B) Proper expression and localization were validated by immunofluorescence of chCAR (green) in H9C2 cells. (A) The CAR expression construct contains the MLC-2 promoter, β-globin intron 2, chicken CAR cDNA (chCAR), and the simian virus 40 polyadenylation sequence (SV40pA). Generation and basic characterization of the noncardiac CAR knockout mouse (ncKO). Our findings have implications for the evolution of virus-host versus physiological interactions involving CAR and could help to improve future coxsackievirus-directed therapies inhibiting virus replication while maintaining CAR's cellular functions.Ĭopyright © 2014, American Society for Microbiology. Here, we show that chicken CAR expression exclusively in the heart can rescue the otherwise embryonic-lethal CAR knockout phenotype but does not support CVB3 infection of adult cardiomyocytes. In the adult heart, CAR is important for virus entry and electrical conduction, but its nonmuscle functions are largely unknown. Animals without CAR die prenatally with major cardiac malformations.
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Its receptor, the coxsackievirus and adenovirus receptor (CAR), not only mediates virus uptake but also relates to cytoskeletal organization and intracellular signaling. Thus, CAR-directed anticoxsackievirus therapy with only minor adverse effects in noncardiac tissue could be further improved by selectively targeting the virus-host interaction while maintaining cardiac function.Ĭoxsackievirus B3 (CVB3) is one of the most common human pathogens causing myocarditis. Comparison of sequence homology and modeling of the D1 domain indicate differences between mammalian and chicken CAR that relate to the sites important for virus binding but not those involved in homodimerization. However, chicken CAR did not mediate virus entry in vivo, so that hearts expressing chicken instead of mouse CAR were protected from infection and myocarditis. In adult animals, cardiac activity was normal, suggesting that chicken CAR can replace the physiological functions of mouse CAR in the cardiomyocyte. Survival of the noncardiac CAR KO (ncKO) mouse indicates an essential role for CAR in the developing heart but not in other tissues. Using this rescue model, we addressed interspecies differences in coxsackievirus uptake and noncardiac functions of CAR. Here, we generated a transgenic mouse that rescued the otherwise embryonic-lethal CAR knockout (KO) phenotype by expressing chicken CAR exclusively in the heart. Noncardiac functions are less well understood, in part due to the lack of suitable animal models. In the heart, CAR is crucial for embryonic development, electrophysiology, and coxsackievirus B infection. The cytoplasmic tail links CAR to the cytoskeleton and intracellular signaling cascades.
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Its extracellular immunoglobulin domains mediate the binding to coxsackievirus and adenovirus as well as homophilic and heterophilic interactions between cells. The coxsackievirus and adenovirus receptor (CAR) is a cell contact protein with an important role in virus uptake.