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 extracellular immunoglobulin domains mediate the binding to coxsackie and adenoviruses as well as homophilic and heterophilic interactions 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. Non-cardiac 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 non-cardiac functions of CAR. Survival of the non-cardiac CAR KO mouse (ncKO) indicates an essential role for CAR in the developing heart, but not in other tissues. In adult animals cardiac activity was normal, suggesting that chicken CAR can replace the physiological functions of mouse CAR in the cardiomyocyte. 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. 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. Thus, CAR-directed anti-coxsackieviral therapy with only minor adverse effects in non-cardiac tissue could be further improved by selectively targeting the virus-host interaction while maintaining cardiac function