Interspecies Differences in Virus Uptake versus Cardiac Function of the Coxsackievirus and Adenovirus Receptor

The coxsackievirus and adenovirus receptor (CAR) is a cell contact protein with an important role in virus uptake. Its extracellu-lar immunoglobulin domains mediate the binding to coxsackievirus and adenovirus as well as homophilic and heterophilic in-teractions between cells. The cytoplasmic tail links CAR to the cytoskeleton and intracellular signaling cascades. In the heart, CAR is crucial for embryonic development, electrophysiology, and coxsackievirus B infection. Noncardiac functions are less well understood, in part due to the lack of suitable animal models. Here, we generated a transgenic mouse that rescued the otherwise embryonic-lethal CAR knockout (KO) phenotype by expressing chicken CAR exclusively in the heart. Using this rescue model, we addressed interspecies differences in coxsackievirus uptake and noncardiac functions of CAR. Survival of the noncardiac CAR KO (ncKO)mouse indicates an essential role for CAR in the developing heart but not in other tissues. In adult animals, car-diac activity was normal, suggesting that chicken CAR can replace the physiological functions of mouse CAR in the cardiomyo-cyte. However, chicken CAR did not mediate virus entry in vivo, so that hearts expressing chicken instead of mouse CAR were protected from infection andmyocarditis. Comparison of sequence homology andmodeling of the D1 domain indicate differ-ences betweenmammalian and chicken CAR that relate to the sites important for virus binding but not those involved in ho-modimerization. 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