Location: Animal Disease Research
Project Number: 2090-32000-030-04-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Aug 15, 2014
End Date: Aug 14, 2015
To continue our collaboration focused on the diagnosis and control of sheep scrapie in the United States and to initiate collaboration concerning Coxiella burnetii (i.e., Q fever) diagnosis and pathogenesis. The focus of ongoing scrapie work is the characterization of scrapie strains in terms of their diagnosis and transmissibility, especially within and from the goat. A key component of C. burnetii research is to delineate the pathogenesis of C. burnetii in small ruminants with a goal of understanding transmission risk from the exposed/infected small ruminant to humans.
Tissue samples from sheep and goats with Transmissible Spongiform Encephalopathy (TSE) will be administered to mice by intracerebral injection. Multiple tissue types will be included, such as samples of brain, lymph node, blood, urine, feces, and muscle. Mouse models used as recipient hosts will include both preexisting and recently created transgenic and inbred mouse lines. Recipient mouse phenotype will be evaluated by measuring clinical response, population disease rate, incubation time, and pathologic profile within the central nervous system (CNS). Pathologic profile of CNS lesion foci is assessed by evaluating anatomic localization, spongiform change, astrocytic gliosis, and deposition of protease resistant prion protein. Avirulent and virulent forms of C. burnetii will be studied in vitro and in vivo to determine the host mechanisms responsible for the clearance, persistence, recrudescence and transmission of Q fever. Work performed in mice will complement studies performed in sheep. Using macrophages obtained from sheep, humans and genetically engineered mice (GEM), we will determine the innate immune system pathways required for the killing and clearance of C. burnetii from macrophages in vitro. Studies performed in vivo will be performed to measure bacterial clearance and persistence of C. burnetii infection using GEMs lacking specific proteins identified as being required for clearance in vitro. Studies using molecular and quantitative approaches will be used to identify genes involved in the host genetics of susceptibility to and persistence of C. burnetii infection in sheep and mice. Genetic studies in mice will be performed using the collaborative cross and genome-wide association studies performed in sheep. Identification of genes in mice and sheep that are associated with increased persistence of infection will be considered likely targets for the development of hypothesis and future studies with the goal to control C. burnetii infection in sheep and humans.