Identification and Characterization of Entry Factors Critical for Rift Valley Fever Virus Infection and Pathogenesis

Project Summary/Abstract
Rift Valley fever virus (RVFV) is a phlebovirus that belongs to the Phenuiviridae (formerly Bunyaviridae) family
of negative-sense RNA viruses. As an emerging mosquito-borne virus, the significance of RVFV is highlighted
by its designation as a NIAID Category A pathogen and its inclusion on the WHO's Blueprint of Priority Diseases.
Recently, the Coalition for Epidemic Preparedness Innovations (CEPI) has also included RVFV as a part of their
emerging infectious diseases vaccine program, further emphasizing the potential impact of RVFV on the global
health and economy. While RVFV is endemic throughout sub-Saharan Africa, competent mosquito vector
species are found in North America, highlighting the potential for emergence of RVFV in non-endemic countries,
including the United States. During outbreaks, RVFV causes severe disease in livestock, including sheep and
cattle, which dramatically impact the socioeconomic framework in resource limited settings. Humans are spill-
over hosts, where infections can result in severe consequences, including hepatic necrosis, hemorrhagic fever,
encephalitis, and retinal vasculitis. Despite its significance to human health and the potential to negatively impact
the socioeconomic fabric of resource-limited countries where the virus is endemic, there is a lack of safe and
efficacious prophylactic and therapeutic treatment options. This gap is in part due to our lack of knowledge on
host factors that contribute to RVFV infection. To address this need, we conducted a genomic screen that defined
several critical factors, including a potential entry factor, which we will characterize by a multidisciplinary
approach. In support, we provide compelling preliminary data, including in vitro validation in host factor sufficient
and deficient cells, transcomplementation studies, direct interaction between RVFV glycoprotein Gn and the host
proteins in vitro, inhibition of the entry factor by endogenous ligands in vitro in multiple cell lines from
evolutionarily distinct hosts, and preliminary results of protection from RVFV infection in two conditional knock
out mouse models. Importantly, we have generated many key reagents, including most cell lines and proteins,
and knock-out mice supporting the feasibility. Importantly, this work will be performed by highly productive and
collaborative investigators with expertise in every aspect of the proposed studies, including biochemistry, RVFV
pathogenesis, immunology, proteomics, structural biology, and virology. Completion of the proposed studies will
define novel host or entry factors for RVFV in target cells with tissue-specific relevance. As a specific receptor
for RVFV has not previously been identified, these studies will provide important information for design of
therapeutic interventions to prevent RVFV infection and disease. At the completion, we expect to fill a key gap
in the field and to provide novel targets for therapeutic development.

Grant Number: 5R01AI161765-05
NIH Institute/Center: NIH
Principal Investigator: Gaya Amarasinghe