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Research Project: Ecology of Vesicular Stomatitis Virus (VSV) in North America


2017 Annual Report

1. Ascertain the viral ecology of disease and factors mediating the emergence of VSV. 1.A. Characterize epidemiological, biotic and abiotic factors associated with the emergence and transmission of VSV in endemic versus non-endemic settings. 2. Develop intervention strategies to minimize the impact of VSV disease outbreaks. 2.A. Develop means to detect and characterize emergent VSV strains and use these data to generate models that predict future outbreaks. 2.B. Identify vector transmission control strategies based on our understanding of vector-host interactions.

1. A comprehensive analysis of Vesicular Stomatitis (VS) outbreaks occurring in the U.S. from 2004-2016 will be conducted to determine the relationship between the geographical location of premises reporting VS outbreaks and the spatial and temporal variability in a large suit of ecological variables. Multiple data streams involving disease occurrence and ecological conditions will be obtained from multiple sources and harmonized for integration and analysis. These data sources include; a) outbreak occurrence data inclusive of geo-location, host species, number of animals affected and onset date, b) ecological data analysis c) biotic and abiotic variables inclusive of animal density, hydrological features and streams, elevation and surface water properties, air temperature and precipitation, vegetation ENSO (El Nino Southern Oscilation) data, soil properties and long term trends in environmental variables. Additional data such as water quality monitoring and U.S. census data for human population distribution may be included. These data will be harmonized and univariate and multivariate statistical analysis will be conducted to determine the best set of explanatory variables for temporal and spatial patterns. These analyses will be used to identify ecological variables associated with VS disease occupancy and spread in the western U.S. and to develop predictive models for disease spread. 2. The characterization of VSV transmission in endemic vs non-endemic settings will be conducted in collaboration with Mexico’s SENASICA-EADC laboratory to conduct genomic sequencing and phylogeographic characterization of viral strains collected through VS surveillance activities in Mexico and to identify the ecological and environmental factors associated with the occurrence of VSV in Mexico. A collaboration with USDA-APHIS will established to determine the phylogeopraphic characteristics of VSV strains causing outbreaks in the U.S. This information will be used to create predictive models for VSV occurrence in Northern Mexico and the U.S. 3. To identify intervention strategies agains VSV outbreaks, we will first assess the success of specific lineages to spread over a large geographic range and determine the factors of viral virulence not found in strains remaining within endemic foci. This analysis will be conducted through comparison of the pathogeneis of lineage, identification of phyenotypic differences among strains and mutation of infectious genetic clone derived from virulent strain lineage observed in swine. The endemic and epidemic lineages will be compared to determine transmissibility by insect vectors.

Progress Report
During 2017 activities were focused on the new research project objectives, collaborative research agreements were established among USDA ARS and APHIS partners as well as a cooperative agreement with Mexico’s animal health service (SENASICA). A “Grand Challenge” project proposal was submitted with the goal of developing a strategy and operational framework for predictive disease ecology and other challenges requiring big data and trans-disciplinary scientific expertise based on spatio-temporal modeling of cross-scale interactions coupled with human and machine learning. The project team includes scientists and veterinarians with expertise in virology and phylogenetics from Plum Island, biology of arthropod vectors of infectious agents from ABDRU, animal disease surveillance and epidemiology from APHIS-VS range management specialists and landscape systems ecologist from Colorado and New Mexico. Objective 1., Subobjective 1.1. During 2017 in close collaboration with the team described above, we Integrated data and information including meteorological and climate data form the last 30 years in the affected region (>1 million sq miles) hydrology data, soil, vegetation, etc. from different sources (APHIS, NGS, ENSO, etc.) across a broad range of temporal and spatial scales associated to 1500 VSV case occurrence in the USA from 2004-2016. The resulting “data cube” was used to carry out univariate and multivariate analyses and a manuscript entitled “Developing early warning strategies for vector-borne diseases through big data integration across scales” is under final preparation for submission to a peer-reviewed journal. Subobjective 1.2. Significant progress was made in the genomic characterization of viral strains of Vesicular Stomatitis Virus (VSV) associated to U.S. outbreaks from 2004-2006 and 2012-2016 obtained through collaboration with the Animal Plant Health Inspection Agency -National Veterinary Services Laboratory (APHIS-NVSL). Next-generation sequencing protocols were developed at PIADC and over 200 viral strains were full-genome sequenced and phylogenetically characterized. The results of this work were presented at the American Society for Virology with the talk entitled: “Phylodynamics Of Vesicular Stomatitis Virus Associated With Outbreaks In The Southwestern US 2012-2015”. A scientific manuscript with the same title in under preparation for submission to a peer-reviewed journal. Work has continued toward understanding the mechanisms of pathogenesis of epidemic VSV strains causing outbreaks in the U.S. In 2015 we showed that Vesicular Stomatitis New Jersey Virus (VSNJV) lineage 1.1 (epidemic) was more virulent than lineage 1.2 (endemic), when inoculated in a natural host model (swine) using skin scarification. Last year we have expanded this work showing that the increased virulence is associated to the ability of lineage 1.1 to inhibit interferon responses. We further showed that a genetically modified VSNJV containing a mutation that impairs the ability to the virus to inhibit interferon (IFN) response resulted in an attenuated phenotype. To further our understanding of the role that interferon play on VSV pathogenesis, we tested a virus that coded for the interferon beta (IFNb) gene for its pathogenesis in pigs. The virus, which is being evaluated as an oncolytic agent in humans and dogs, was completely attenuated in pigs. The results were published in the journal “Human Gene Therapy Clinical Development”. Important progress was made in understanding the ecological factors associated to VSV occurrence in the southwestern U.S. Under an ARS Grand Challenge Initiative, we continued working with a team of ecologists, entomologists and epidemiologists from various ARS locations. These include the Jornada Rangeland Research Station in New Mexico, the Arthropod-borne Disease Research Unit in Manhattan Kansas, and the Foreign Animal Disease Research Unit in Orient Point, New York, as well as APHIS Veterinary Services in Ft. Collins, Colorado. An initial analysis of the last two VS outbreak cycles in the U.S.(2004-2006 and 2012-2015) was concluded. A manuscript describing the process, initial results and its application to an early warning mode for disease occurrence is under preparation.

1. The silver bullet: utilizing vesicular stomatitis virus to treat cancer. Vesicular stomatitis virus (VSV) is an animal pathogen that causes vesicular disease in horses, cattle and pigs. VSV is a bullet-shaped enveloped virus that grows rapidly producing powerful immune response that can be used as a vaccine to prevent and/or treat infectious disease and cancer in humans and animals. Modified VSV has been shown to replicate selectively in and kill cancer cells and were not pathogenic during clinical trials in humans and dogs. However, there was concern that these VSV vectors could be pathogenic and transmissible to farm animals (e.g. pigs). ARS scientists at Plum Island, Orient, New York collaborated with scientists at Mayo Clinic and Vyriad, Rochester, Minnesota and showed that VSV is safe not only to humans and dogs, but also in pigs. These studies pave the way for further development of this promising cancer therapy.

Review Publications
Velazquez-Salinas, L., Niak, S., Peng, K., Pauszek, S.J., Rodriguez, L.L. 2017. Oncolytic recombinant vesicular stomatitis virus (VSV) is nonpathogenic and non-transmissible in pigs, a natural host of VSV. Human Gene Therapy. 28(2):108-115.