부산대학교 도서관

Viral infection of the heart is a common but underappreciated cause of heart failure. Viruses can cause direct cardiac damage by lysing infected cardiomyocytes. Inflammatory immune responses that limit viral replication can also indirectly cause damage during infection, making regulatory factors that fine-tune these responses particularly important. Identifying and understanding these factors that regulate cardiac immune responses during infection will be essential for developing targeted treatments for virus-associated heart failure. Our laboratory has discovered Brain Expressed X-linked protein 1 (BEX1) as a novel stress-regulated pro-inflammatory factor in the heart. Here we report that BEX1 plays a cardioprotective role in the heart during viral infection. Specifically, we adopted genetic gain- and loss-of-function strategies to modulate BEX1 expression in the heart in the context of coxsackievirus B3 (CVB3)-induced cardiomyopathy and found that BEX1 limits viral replication in cardiomyocytes. Interestingly, despite the greater viral load observed in mice lacking BEX1, inflammatory immune cell recruitment in the mouse heart was profoundly impaired in the absence of BEX1. Overall, the absence of BEX1 accelerated CVB3-driven heart failure and pathologic heart remodeling. This result suggests that limiting inflammatory cell recruitment has detrimental consequences for the heart during viral infections. Conversely, transgenic mice overexpressing BEX1 in cardiomyocytes revealed the efficacy of BEX1 for counteracting viral replication in the heart in vivo. We also found that BEX1 retains its antiviral role in isolated cells. Indeed, BEX1 was necessary and sufficient to counteract viral replication in both isolated primary cardiomyocytes and mouse embryonic fibroblasts suggesting a broader applicability of BEX1 as antiviral agent that extended to viruses other than CVB3, including Influenza A and Sendai virus. Mechanistically, BEX1 regulated interferon beta (IFN-β) expression in infected cells. Overall, our study suggests a multifaceted role of BEX1 in the cardiac antiviral immune response. Author summary: Many viral species infect the heart and cause heart failure, which is an irreversible condition with high prevalence, cost, and morbidity. They damage the heart directly by killing infected cells and indirectly by causing excessive immune reactions. This has made it difficult to develop generalizable treatments, and there is a need to better understand the molecular mechanisms through which the heart naturally defends itself from viruses. Here we have identified the protein Brain Expressed X-Linked 1 (BEX1) as a novel antiviral protein that protects the heart from infection. Mice lacking BEX1 are more susceptible to virus-induced cardiac damage, they have problems recruiting immune cells to the heart, and they have greater difficulty clearing the virus. Conversely, overexpression of BEX1 confers protection from infection. Importantly, BEX1 maintains its antiviral role in isolated cells and in response to a variety of viruses, which indicates that its antiviral effect is broad and not entirely dependent on the immune system. Moreover, it regulates the production of the key antiviral protein interferon beta, which suggests that BEX1 may be an underappreciated master regulator of the antiviral response. [ABSTRACT FROM AUTHOR]