Comparative genome analysis of three eukaryotic parasites with differing abilities to transform leukocytes reveals key mediators of theileria-induced leukocyte transformation
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Type
ArticleAuthors
Hayashida, KyokoHara, Yuichiro
Abe, Takashi
Yamasaki, Chisato
Toyoda, Atsushi
Kosuge, Takehide
Suzuki, Yutaka
Sato, Yoshiharu
Kawashima, Shuichi
Katayama, Toshiaki
Wakaguri, Hiroyuki
Inoue, Noboru
Homma, Keiichi
Tada-Umezaki, Masahito
Yagi, Yukio
Fujii, Yasuyuki
Habara, Takuya
Kanehisa, Minoru
Watanabe, Hidemi
Ito, Kimihito
Gojobori, Takashi

Sugawara, Hideaki
Imanishi, Tadashi
Weir, William
Gardner, Malcolm
Pain, Arnab

Shiels, Brian
Hattori, Masahira
Nene, Vishvanath
Sugimoto, Chihiro
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computational Bioscience Research Center (CBRC)
Pathogen Genomics Laboratory
Date
2012-09-04Online Publication Date
2012-09-04Print Publication Date
2012-09-04Permanent link to this record
http://hdl.handle.net/10754/325462
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Show full item recordAbstract
We sequenced the genome of Theileria orientalis, a tick-borne apicomplexan protozoan parasite of cattle. The focus of this study was a comparative genome analysis of T. orientalis relative to other highly pathogenic Theileria species, T. parva and T. annulata. T. parva and T. annulata induce transformation of infected cells of lymphocyte or macrophage/monocyte lineages; in contrast, T. orientalis does not induce uncontrolled proliferation of infected leukocytes and multiplies predominantly within infected erythrocytes. While synteny across homologous chromosomes of the three Theileria species was found to be well conserved overall, subtelomeric structures were found to differ substantially, as T. orientalis lacks the large tandemly arrayed subtelomere-encoded variable secreted protein-encoding gene family. Moreover, expansion of particular gene families by gene duplication was found in the genomes of the two transforming Theileria species, most notably, the TashAT/TpHN and Tar/Tpr gene families. Gene families that are present only in T. parva and T. annulata and not in T. orientalis, Babesia bovis, or Plasmo-dium were also identified. Identification of differences between the genome sequences of Theileria species with different abilities to transform and immortalize bovine leukocytes will provide insight into proteins and mechanisms that have evolved to induce and regulate this process. The T. orientalis genome database is available at http://totdb.czc.hokudai.ac.jp/. 2012 Hayashida et al. T.Citation
Hayashida K, Hara Y, Abe T, Yamasaki C, Toyoda A, et al. (2012) Comparative Genome Analysis of Three Eukaryotic Parasites with Differing Abilities To Transform Leukocytes Reveals Key Mediators of Theileria-Induced Leukocyte Transformation. mBio 3: e00204-12-e00204-12. doi:10.1128/mBio.00204-12.Publisher
American Society for MicrobiologyJournal
mBioPubMed ID
22951932PubMed Central ID
PMC3445966ae974a485f413a2113503eed53cd6c53
10.1128/mBio.00204-12
Scopus Count
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Advisor: Pain, Arnab
Committee members: Morrison, Ivan; Langsley, Gordon; Merzaban, Jasmeen; Ghaffour, NorEddineTropical Theileriosis is a parasitic disease of calves with a profound economic impact caused by Theileria annulata, an apicomplexan parasite of the genus Theileria. Transmitted by Hyalomma ticks, T. annulata infects and transforms bovine lymphocytes and macrophages into a cancer-like phenotype characterized by all six hallmarks of cancer. In the current study we investigate the transcriptional landscape of T. annulata-infected lymphocytes to define genes and miRNAs regulated by host cell transformation using next generation sequencing. We also define genes and miRNAs differentially expressed as a result of the attenuation of a T.annulata-infected macrophage cell line used as a vaccine. By comparing the transcriptional landscape of one attenuated and two transformed cell lines we identify four genes that we propose as key factors in transformation and virulence of the T. annulata host cells. We also identify miR- 126-5p as a key regulator of infected cells proliferation, adhesion, survival and invasiveness. In addition to the host cell trascriptome we studied T. annulata transcriptome and identified the role of ROS and TGF-β2 in controlling parasite gene expression. Moreover, we have used the deep parasite ssRNA-seq data to refine the available T. annulata annotation. Taken together, this study provides the full list of host cell’s genes and miRNAs transcriptionally perturbed after infection with T. annulata and after attenuation and describes genes and miRNAs never identified before as players in this type of host cell transformation. Moreover, this study provides the first database for the transcriptome of T. annulata and its host cells using next generation sequencing. -
miR-34c-3p regulates PKA activity independent of cAMP via ablation of PRKAR2B in Theileria annulata-infected leukocytes and Plasmodium falciparum-infected erythrocytesHaidar, Malak; Ben Rached, Fathia; Wagner, Matthias; Mourier, Tobias; Rchiad, Zineb; Mfarrej, Sara; Chitnis, Chetan E.; Pain, Arnab; Langsley, Gordon (Cold Spring Harbor Laboratory, 2020-04-12) [Preprint]MicroRNAs (miRNAs) are small non-coding RNAs that can play critical roles in regulating various cellular processes including during many parasitic infections. Here, we report a regulatory role for miR-34c-3p in cAMP-independent regulation of PKA activity in Theileria annulata and Plasmodium falciparum infections of bovine leukocytes and human erythrocytes, respectively. We identified prkar2b (cAMP-dependent protein kinase A type II-beta regulatory subunit), as a novel miR-34c-3p target gene and demonstrated how infection-induced up-regulation of miR-34c-3p in leukocytes repressed PRKAR2B expression to increase PKA activity and promote the virulent disseminating tumour phenotype of T. annulata-transformed macrophages. When human erythrocytes are infected by P. falciparum they accumulate miR-34c-3p that ablates both prkar2b and parasite Pfpkar mRNA. However, erythrocytes lack protein translation machinery so only miR-34c-3p-mediated loss of Pfpkar transcripts results in an increase in PfPKA kinase activity. Inhibition of miR-34c-3p increases Pfpkar expression to reduce PfPKA activity leading to slowing of intra-erythrocyte parasite development and a reduction in invasion of fresh red blood cells. Finally, we demonstrate that miR-34c-3p regulation of prkar2b expression is generalizable, by showing that it can negatively regulate prkar2b expression and PRKAR2B protein levels in human cancer cell lines and that brown adipose tissue displays high levels of miR-34c-3p and corresponding low levels of prkar2b mRNA compared to white adipose tissue. Induction of miR-34c-3p therefore, represents a novel cAMP-independent way of regulating PKA activity in a range of cell types associated with cancer, diabetes and parasitic diseases.