LRP1 facilitates Jamestown Canyon virus infection of neurons

Jamestown Canyon virus (JCV) is a bunyavirus and arbovirus that causes viral neuroinvasive disease in North America. JCV neuropathogenesis is understudied, and no pro-viral host factors for cellular infection have been identified. Here, we assessed the role of low-density lipoprotein receptor-related protein 1 (LRP1; also known as CD91), which has been identified as a host entry factor for other bunyaviruses, in mediating JCV infection with a focus on neurons. Both neuronal and non-neuronal immortalized cell lines deficient for murine Lrp1 displayed reduced binding, internalization, and infection with JCV. Furthermore, a soluble extracellular domain of human LRP1 can bind directly to JCV, and the same region of LRP1 can neutralize JCV infection. Primary neurons, where Lrp1 was highly expressed, were permissive for JCV infection. Treatment of primary neurons with the murine Lrp1 ligand receptor-associated protein (RAP) resulted in reduced infectivity with JCV. Finally, treatment of Lrp1 knockout cells with RAP further reduced JCV infection, suggesting that other low-density lipoprotein receptors may mediate JCV entry in the absence of Lrp1. Together, these results support LRP1 as an important cellular factor for efficient neuronal infection by JCV. Emerging support for the use of LRP1 for viral entry by multiple bunyaviruses also makes LRP1 a promising target for antiviral development.IMPORTANCEJamestown Canyon virus (JCV), an emerging mosquito-transmitted virus in North American white-tailed deer, causes several cases of severe neurologic disease in humans each year. Our results on the use of low-density lipoprotein receptor (LDLR)-related protein 1 by JCV for efficient cellular infection of neurons underscore the significance of the LDLR family of receptors in viral infection. Recent studies also highlight the emerging use of the LDLR family of receptors for virus entry by the bunyavirus and alphavirus family members. Defining cellular factors that mediate infection by mosquito-transmitted viruses is critically important to the prototype pathogen approach for combating infectious diseases and countermeasure development.