Characterizing the role of LDL related receptor 1 (Lrp1) as host entry factor for multiple bunyaviruses

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Project Summary/Abstract Bunyaviruses (Order: Bunyavirales) are a growing and diverse family of animal and human pathogens with pandemic potential. With over 300 members and an expanding distribution of mosquito and tick vectors due to climate change, these viruses are responsible for increasing outbreaks of human disease and present a significant threat to human health. Rift Valley Fever virus (RVFV) is one of the well-studied bunyaviruses and is designated as an NIAID Category A pathogen and included in the WHO’s Blueprint of Priority Diseases. The Coalition for Epidemic Preparedness Innovations (CEPI) included RVFV as part of their emerging infectious diseases vaccine program, further emphasizing the potential impact on the global health and economy. Oropouche virus (OROV) is found in South America and has caused more than 30 large epidemics resulting in over 500,000 human cases, making it the second most common arboviral disease in South America behind Dengue fever. However, the true case number is likely much higher due to Oropouche fever being misdiagnosed as Chikungunya or Dengue. A third member, La Crosse virus (LACV) is found primarily in North America and is the primary cause of pediatric viral encephalitis in the United States. Neither OROV nor LACV have been as well studied as RVFV, and thus a significant gap remains in our broad understanding of bunyavirus pathogenesis. Currently there are no approved therapeutic drugs for treatment of RVFV, OROV, or LACV disease, further highlighting the need for our proposed studies. To address this need, we conducted a genomic screen that defined several critical factors, including Lrp1, an LDL family member. In support we provide compelling preliminary data including in vitro validation in Lrp1 sufficient and deficient cells, transcomplementation studies, and direct interaction between RVFV glycoprotein Gn in vitro. We also show that inhibition of Lrp1 by endogenous ligands in vitro in multiple cell lines from evolutionarily distinct hosts, and in vivo data demonstrating the importance of Lrp1 for viral tropism and disease in mice. Here we will characterize the importance of Lrp1 for entry of multiple bunyaviruses, define molecular mechanisms, and validate the significance in vitro and in vivo. This work will be performed by highly productive and collaborative investigators with expertise in every aspect of the proposed studies, including biochemistry, viral pathogenesis, immunology, proteomics, structural biology, and virology. At completion, we expect to validate Lrp1 as pan-bunyavirus entry factor, filling a key gap in the field and to provide novel targets for therapeutic development.