Equine Protozoal Myeloencephalitis: investigating immunopathogenesis and treatment efficacy in mouse models and clinically affected horses
Hay, Alayna Nicole
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Equine protozoal myeloencephalitis (EPM), predominantly caused by the protozoa Saracocystis neurona, is a common neurologic disease in horses from North America. Equine exposure to the parasite occurs frequently as the protozoa is excreted in opossum (Didelphis virginiana) feces and contaminates the horse's environment. However, clinical neurologic disease only emerges in a small fraction of exposed horses. The seemingly protective immune response that develops in some exposed horses but not all is not fully defined. Previous reports utilizing horse EPM models and immune compromised mouse models, which develop disease simulating EPM after infection with S. neurona, have reported a role of T-lymphocytes and the cytokine interferon gamma, in disease protection. As part of this dissertation, the role of T-lymphocytes and IFNγ was further elucidated. It was determined that IFNγ production is essential for T-lymphocytes to offer protection against S. neurona induced encephalitis, in immune compromised mice. Another factor hindering prognosis of EPM affected horses is treatment failure. The efficacy of the antiprotozoal decoquinate, was tested and found to be ineffective at preventing S. neurona encephalitis, in immune compromised mice. However, the antiprotozoal, diclazuril, was found to be effective at preventing S. neurona encephalitis in immunocompromised mice but once treatment was terminated, infection persisted, and neurologic disease developed. In-situ methods were employed to extensively evaluate the immunopathology of spinal cord tissue samples collected from EPM affected horses. A novel in-situ hybridization technique was successfully utilized to identify S. neurona in tissue samples collected from horses with EPM. This technique will create new opportunities for investigating the immunopathology of EPM. Overall results from the studies conducted in this dissertation suggest that IFNγ production from T lymphocytes is essential for them to offer protection against S. neurona encephalitis. Additionally, further insight on FDA approved and non-FDA approved treatment options for S. neurona infection was gained through the use of the B6Ifnγ -/- mouse model. Collectively, these studies expanded on the knowledge of an understudied equine neurologic disease.
General Audience Abstract
Horses are susceptible to the neurologic disease Equine Protozoal Myeloencephalitis, more commonly referred to as EPM by equine enthusiasts. The disease results from ingestion of the parasite, Saracocystis neurona, which contaminates the horse's natural environment; therefore, horses are likely to come in contact with the parasite while eating or drinking. Not all horses that encounter S. neurona develop neurologic disease, some will be protected by their immune system with the only evidence of exposure being serological antibodies. In efforts to not experimentally induce EPM in horses, an immunocompromised mouse model is often used instead. Through the use of the immunocompromised mouse model, researchers have discovered that the immune cell, T lymphocytes, and signaling molecule, interferon gamma, are important for protection against S. neurona infection. In one study conducted for this dissertation it was found that T lymphocytes need to be able to produce interferon gamma in order to provide protection. Another issue that the immunocompromised mouse model has helped address, is EPM treatment efficacy. The inability of antiprotozoal drugs that are utilized for EPM treatment to fully eliminate the parasite from the horse's body is thought to cause reoccurring disease in some horses. One non-FDA approved treatment was evaluated here and determined not to be effective in the immunocompromised mouse model. One FDA approved treatment option, which is commonly used to treat EPM, was evaluated as well. This drug was proven to be effective at preventing disease while mice were being treated but termination of treatment led to development of neurologic disease, exemplifying treatment failure. One final study was conducted to examine the different types of immune cells and signaling molecules in spinal cord tissue samples collected, from horses which had to be euthanized due to poor prognosis related to EPM. In this study a novel experimental technique was successfully used which will help progress EPM research. Overall results of these studies offered more explanation on the immune response that protects against neurologic disease from S. neurona infection and demonstrated that not all treatments are effective and reoccurring disease may be a result of treatment failure.
- Doctoral Dissertations