التفاصيل البيبلوغرافية
| العنوان: |
Engineering Attenuated Virulence of a Theileria annulata–Infected Macrophage. |
| المؤلفون: |
Echebli, Nadia, Mhadhbi, Moez, Chaussepied, Marie, Vayssettes, Catherine, Di Santo, James P., Darghouth, Mohamed Aziz, Langsley, Gordon |
| المصدر: |
PLoS Neglected Tropical Diseases; 11/6/2014, Vol. 8 Issue 11, p1-8, 8p |
| مصطلحات موضوعية: |
THEILERIA, PATHOLOGY, MACROPHAGES, TROPICAL medicine, CATTLE diseases, THEILERIOSIS, FOOT & mouth disease |
| مصطلحات جغرافية: |
MIDDLE East, MAGHREB (North Africa) |
| مستخلص: |
Live attenuated vaccines are used to combat tropical theileriosis in North Africa, the Middle East, India, and China. The attenuation process is empirical and occurs only after many months, sometimes years, of in vitro culture of virulent clinical isolates. During this extensive culturing, attenuated lines lose their vaccine potential. To circumvent this we engineered the rapid ablation of the host cell transcription factor c-Jun, and within only 3 weeks the line engineered for loss of c-Jun activation displayed in vitro correlates of attenuation such as loss of adhesion, reduced MMP9 gelatinase activity, and diminished capacity to traverse Matrigel. Specific ablation of a single infected host cell virulence trait (c-Jun) induced a complete failure of Theileria annulata–transformed macrophages to disseminate, whereas virulent macrophages disseminated to the kidneys, spleen, and lungs of Rag2/γC mice. Thus, in this heterologous mouse model loss of c-Jun expression led to ablation of dissemination of T. annulata–infected and transformed macrophages. The generation of Theileria-infected macrophages genetically engineered for ablation of a specific host cell virulence trait now makes possible experimental vaccination of calves to address how loss of macrophage dissemination impacts the disease pathology of tropical theileriosis. Author Summary: Tropical theileriosis is a leukaemia-like disease of cattle caused by the Apicomplexa parasite Theileria annulata. Live attenuated vaccines are used to control the mortality and morbidity of tropical theileriosis and each endemic country produces its own vaccine by isolating a virulent clinical isolate and then growing the infected and transformed macrophages for many months in the laboratory. With time, virulence is progressively lost, and loss is evaluated from time to time by injecting infected macrophages into calves and monitoring any resulting pathology. If the calves demonstrate clinical symptoms, in vitro culture of vaccine lines continues, and eventually attenuation is achieved after approximately two years. The process is empirical, and with time in culture the infected macrophage lines lose their vaccine potential such that when cattle are injected the immune response to the vaccine can be compromised. To circumvent these problems we engineered the rapid loss of a host macrophage virulence trait and obtained complete attenuation of dissemination of T. annulata–transformed macrophages when tested in an immune-compromised mouse model. This rational, rather than empirical, approach now allows injecting into calves Theileria-infected macrophages engineered for attenuation to evaluate the role of Theileria-infected macrophage dissemination in the pathology of tropical theileriosis. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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