RP3: Cedar henipavirus animal model

PROJECT SUMMARY/ABSTRACT - RP3 (Cedar Henipavirus Animal Model) Henipaviruses are single-stranded, negative-sense enveloped RNA viruses of the paramyxovirus family. Two henipaviruses, Nipah virus (NiV) and Hendra virus (HeV), cause a systemic and often fatal respiratory and/or encephalitic disease in humans and ten other mammalian species. Importantly, NiV and HeV are significant biothreats to humans and economically important livestock in Australia and Southeast Asia. There are currently no vaccines or therapeutics approved for human use. Notably, development of countermeasures for NiV and HeV is hampered by the fact that these viruses require BSL-4 containment, meaning that very few research groups worldwide have access to the required biocontainment facilities to perform preclinical studies with these important human viral pathogens. To address this problem, we are developing a BSL-2 animal model that is based on Cedar virus (CedV), which is a non-pathogenic henipavirus. Specifically, we are employing recombinant Cedar viruses (rCedVs) in which the NiV and HeV fusion (F) and receptor-binding glycoprotein (G) are expressed in the rCedV genome, replacing CedV F and G. Additionally, we have also incorporated our recently developed in vivo bioluminescence methodology to longitudinally trace the dynamics and anatomical progression of rCedV-luciferase (rCedV-luc) infections in individual animals. Using various approaches to inhibit the host innate immune response in mice, we have demonstrated sustained replication of rCedV-luc and the rCedV-NiV-luc and rCedV-HeV-luc chimeras. Importantly, whereas rCedV-luc does not establish stable expression in the brain, both of the chimeric viruses do. Moreover, preliminary findings show that rCedV-NiV- luc causes neurological dysfunction and death in specific strains of mice. The rCedV-luc platform is thus an authentic henipavirus system that can be used to study henipavirus in vivo biology safely and expediently under BSL-2 containment. Our overall hypothesis is that rCedV-luc infection of mice lacking specific innate immune responses represents a BSL-2 platform for the study of henipavirus biology and pathogenesis, as well as for development and testing of anti-viral countermeasures. We will address this hypothesis through three Specific Aims: Aim 1: To optimize the use of immunodeficient mice and rCedV-NiV-luc/rCedV-HeV-luc chimeras as a robust BSL2 model of pathogenic henipavirus disease; Aim 2: To determine the mechanism of rCedV-NiV neurovirulence; Aim 3: To define the efficacy and mechanisms of mAb-based therapeutics for CNS-resident henipavirus infections. Aims involve synergistic collaborations with several other research projects and cores in this U19 program. Successful completion of these Aims will establish the rCedV-luc mouse model as a robust BSL-2 platform for the exploration of henipavirus pathogenesis and countermeasures.