RNA viruses use a variety of interactions with host proteins to gain entry, to evade immune responses, to promote viral replication, and to promote viral egress and spread. These interactions with virally encoded proteins often modulate cell-intrinsic and cell-extrinsic host signaling pathways. Our recent genome-wide ‘omics studies identified a number of host factors that are important for RNA viral infections, including an LDL family receptor that promotes vector-borne viral infections. Our results coupled with emerging data from the field reveal that multiple bunyavirus infections are facilitated by LDL related protein 1 (Lrp1) and its family members. Following our initial observation, we have pursued biochemical and structural studies to define how Lrp1 interaction with viral factors contributes to infection in vitro and in vivo. Deletion of Lrp1 in cells result in significant reduction in infection. In mice, tissue specific deletion of Lrp1 prevented hepatic infection, but did not prevent death, suggesting a role for non-hepatic Lrp1 in systemic dissemination, including neuroinvasion. The impact of LDL related receptor use by bunyaviruses will be discussed in the context of tropism and dissemination. Our findings will be further compared to emerging data that support the potential use of other LDL family proteins by a diverse group of viruses. Collectively, these studies provide new insights into vector-borne viral infections and provide previously unrecognized opportunities to define therapeutic targets.

Learning Objectives:

1. Demonstrate how molecular mechanisms control viral entry.

2. Demonstrate how biochemical and cell biological tools provide insights into host-pathogen interactions.

3. Define pros and cons of a reductionist approach to work with pathogens and how insights from such can provide potential clinical insights.