Specific interactions of mouse organ proteins with the 5'untranslated region of coxsackievirus B3 : Potential determinants of viral tissue tropism

Coxsackievirus B3 (CVB3) infects multiple organs of humans and causes different diseases such as myocarditis, pancreatitis, and meningitis. However, the mechanisms of organ-specific tropism are poorly understood. Coxsackievirus and adenovirus receptor (CAR) have been known to be important determinants for tissue tropism. However, current data on CAR mRNA expression in certain organs of mouse did not correlate well with the susceptibility of the respective tissues, suggesting that intracellular proteins may also play important roles in the regulation of viral infectivity through interaction with viral RNA. To search for such proteins and their interacting sites, we performed in situ hybridization to detect viral RNA in the organs of 4-week- and 10-week-old CVB3-infected mice and then correlated the data to patterns of host protein-viral RNA interactions. We found that heart and pancreas are the most heavily infected organs while the kidney remains highly resistant to the virus. The brain exhibited localized foci of viral replication, while the heart and liver showed random distribution of CVB3 RNA. The exocrine pancreas is highly susceptible to CVB3 infection but the endocrine cell type is resistant. In contrast to infections in other organs, mouse heart appears more resistant to CVB3 infection with increasing age. This resistance to infection in the kidney and older heart correlates well with the interaction of a 28 kDa mouse protein with the antisense sequence of nucleotides 210-529 of CVB3 5UTR. In addition, more intensified protein interactions were found within the nucleotides 530-630, a region that contains the internal ribosome entry site, which supports the previous findings that this segment plays critical roles in regulation of viral replication.