Exosomes mediate Coxsackievirus B3 transmission and expand the viral tropism

Author summaryEnteroviruses of the family Picornaviridae, in particular coxsackieviruses of Group B (CVB), are highly prevalent human pathogens associated with a variety of acute and chronic forms of diseases. The presence of receptors on specific host cells and abundance of these cells in tissues are major determinants of the route of viral entry into a host. However, our previous data and other studies revealed that virus receptor-negative cells or tissues can be infected with CVB3, which can also effectively replicate. To study this interesting finding, we explored the possibility that exosomes are involved in CVB3 tropism and that exosomes functionally enhance CVB3 transmission. An increasing body of evidence has shown that exosomes released from virus-infected cells contain viral particles or genomes move to neighboring cells, contributing to virus dissemination. In our study, we found that exosomes were prevalent and robust vehicles for the delivery of CVB3 virions, resulting in effective infection of host cells. Additional data confirmed that delivery of CVB3 virions attached to exosomes surmounted barriers to viral tropism. Our novel findings provide new insight into how coxsackieviruses control and exploit exosomes for transmission in an infected host. Specific virus-receptor interactions are important determinants in viral host range, tropism and pathogenesis, influencing the location and initiation of primary infection as well as viral spread to other target organs/tissues in the postviremic phase. Coxsackieviruses of Group B (CVB) and its six serotypes (CVB1-6) specifically interact with two receptor proteins, coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF), and cause various lesions in most permissive tissues. However, our previous data and other studies revealed that virus receptor-negative cells or tissues can be infected with CVB type 3 (CVB3), which can also effectively replicate. To study this interesting finding, we explored the possibility that exosomes are involved in CVB3 tropism and that exosomes functionally enhance CVB3 transmission. We found that exosomes carried and delivered CVB3 virions, resulting in efficient infection in receptor-negative host cells. We also found that delivery of CVB3 virions attached to exosomes depended on the virus receptor CAR. Importantly, exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. In vivo experiments demonstrated that inhibition of exosome coupling with virions attenuated CVB3-induced immunological system dysfunction and reduced mortality. Our study describes a new mechanism in which exosomes contribute to viral tropism, spread, and pathogenesis.