Location: Foreign Arthropod Borne Animal Disease Research
Project Number: 3022-32000-024-021-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Sep 2, 2024
End Date: Aug 31, 2026
Objective:
This agreement aims to explore the ecological and evolutionary factors that influence the emergence of arboviruses in livestock. Arboviruses pose a significant threat to US agriculture, and in particular, the livestock industry. Despite the importance of arboviruses to animal health, there is a limited understanding of the host and viral-encoded factors that influence their pathogenesis and emergence. Additionally, vaccines and therapeutics remain largely unavailable for the majority of emerging arbovirus threats to the US, largely due to unavailable and reliable animal models. To circumvent these threats, this agreement will support research needed in two main research project categories: (1) Understanding arbovirus genetic diversity to further dissect the molecular mechanisms underlying differences in viral fitness, pathogenesis, arboviral spread and emergence potential. (2) Develop, improve, and validate animal models to help inform intervention testing, and our understanding of arboviral pathogenesis and/or virus-host interactions. The research proposed in all the above-listed categories will create a strong foundation to inform predictive modeling to truly assess the growing risk of arbovirus emergence in US agriculture in a rapidly changing world.
Approach:
Research project 1. Understanding arbovirus genetic diversity to dissect the molecular mechanisms underlying differences in viral fitness, pathogenesis, spread and emergence- Emerging viruses will be sequenced using next-generation sequencing technologies to determine complete genome sequences for large numbers of each virus species. Viruses will be selected to represent different geographical areas, a wide temporal period, and isolated from a variety of hosts and vectors, including areas near the livestock/wildlife interface. This will help explore associations between mutations and geographical variation or their impact of animal livestock encroachment into wildlife areas. Sampling over time will allow for modeling of how virus circulation (host-vector-virus) interactions will be affected in a changing climate, and identify if specific mutations are driving emergence or persistence. Next-generation sequencing approaches will be used to generate sequence data using multiple platforms and allow us to expand studies on arbovirus evolution and spread. The complete genome sequence data will be subjected to sophisticated computational and phylogenetic analysis to understand viral evolution, persistence, and spatio-temporal patterns of spread. The data generated in this project will also be useful to provide a robust foundation of arbovirus genetic diversity data for critically important arboviruses that could emerge and threaten animal and public health. Data generated here will also be key to identifying mutations associated with specific phenotypes, emphasizing studies on changes in viral fitness/pathogenesis in vectors and animals. Finally, the virus population variability will be used to inform risk models in future studies. Research project 2. Develop, improve, and validate animal models to better inform intervention testing and our understanding of arboviral pathogenesis or virus-host interactions- Bunyavirus, such as Rift Valley Fever Virus (RVFV), emergence continues to defy accurate prediction, resulting in significant delays before interventions can be tested for their efficacy. To date, there is only a single published small animal model for studying Cache Valley Virus (CVV) pathogenesis in an immune-compromised mouse model. Therefore, there is a need to develop immune-competent animal models that better represent natural progression of disease in various animal groups which can be used as a Bunyavirus model to learn about RVFV. These models can be employed as pathogenesis models to reproduce various aspects of human-like or species-specific disease symptoms, and can mirror the differences in infectivity, virulence among viruses and/or viral strains. We propose to develop multiple pathogenesis models in various animal species using several contemporary arboviral strains. We will characterize the duration and magnitude of viremia, viral persistence, incubation period and short-term humoral immune responses. Establishing these animal models will allow us to explore mechanisms of transmission among various arbovirus pathogens.
