Chapter 42 : -Induced Leukocyte Transformation: an Example of Oncogene Addiction?

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In the case of , the initial invasion and developmental steps can be successfully completed in caprine (goat) lymphocytes in vitro after proteolytic cleavage of surface proteins. Importantly, long-term culture of -infected field isolates that leads to attenuation is associated with a significant reduction of the matrix metalloproteases (MMP) activities. A recurrent theme in research has been the search for putative parasite oncogene(s). A number of receptor-associated and cytosolic kinases, as well as transcription factors, were found to be permanently active in various -infected cell lines. The development of inside its host cell involves highly interdependent interactions between the intracellular parasite and the parasitized cell. With the determination of the genome sequences of and in 2005, combined with the availability of the genome, research on -infected bovine leukocytes has entered the postgenomic era. These resources make it possible to screen both bovine and parasite microarrays. Screening of bovine arrays will allow the identification of host cell genes that are either up or down regulated during infection and leukocyte transformation. Screening of microarrays with mRNA isolated from virulent and attenuated macrophage vaccine lines should allow the identification of parasite genes whose expression is down regulated during host cell attenuation (i.e., loss of metastatic potential).

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42
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Image of FIGURE 1

Time course analysis of the cell cycle distribution of buparvaquone-treated -infected cell lines. infected cell lines were kept untreated or treated with buparvaquone. After the indicated time, the cells were fixed and DNA was labeled with propidium iodide. Cell cycle distribution was analyzed by flow cytometry.

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42
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Image of FIGURE 2

Contrast echography following intravenous injection of microbubbles that allow blood vessels to be detected. The image was made with the help of Gilles Renault of the small animal imagery platform at the Cochin Institute. T. parva-transformed B cells were injected into thighs of Rag2/gammaC mice ( ) and tumor development followed every week for 8 weeks by contrast echography. The highly vascularized tumor shown is at 6 weeks postinjection.

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42
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Image of FIGURE 3

Activated signaling pathways in Theilerid-infected cells. Receptor-associated kinases including JAK, PI3-K, and Src are classically activated upon growth factor receptor engagement. In -infected cells, cytokine autocrine loops participate in -dependent proliferation and may contribute to the activation of receptor-associated, as well as cytoplasmic kinases among which are JNK, CK2, and PKA. Transcription factors like STAT, c-Myc, and AP-1 are positively regulated by phsophorylation mediated by JAK, CK2, and JNK, respectively. Phsophorylation controls their nuclear translocation, their stability, and/or their transactivating potential. Whether the intracellular macroschizont directly modulates the activation status of receptor-associated and cytosolic kinases or their target transcription factors is hypothetical. In contrast, the localization of the IKK signalosome formed by IKKa, IKKβ, and NEMO at the surface of the macroschizont suggests a direct influence of the parasite over the activity of this kinase complex that is responsible for IκBα phosphorylation and degradation and the ensuing nuclear translocation of the NF-κB p50-p65 dimer.

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42
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Image of FIGURE 4

-encoded polypeptides exported to the host cell. TaSE protein was shown to localize to the parasite surface but was also found associated with microtubules in discrete areas. TashAT are found in the nucleus of the infected cell. There has been some suggestion that the catalytic subunit of CK2 might be exported into the host cell.

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42
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Kinases and transcription factors activated in -infected leukocytes

Citation: Chaussepied M, Langsley G. 2011. -Induced Leukocyte Transformation: an Example of Oncogene Addiction?, p 537-546. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch42

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