近日,，諾丁漢大些生物學(xué)院的科學(xué)家們與萊斯特大學(xué),，牛津大學(xué)，帝國(guó)理工大學(xué)和荷蘭萊頓大學(xué)在國(guó)際雜志《PLoS Pathogens》上共同發(fā)表了他們的研究成果,?？茖W(xué)家們依靠寄生蟲生命周期中一個(gè)新蛋白的發(fā)現(xiàn)，鎖定了戰(zhàn)勝全球毀滅性疾病瘧疾的新目標(biāo),。
研究揭示了在瘧疾寄生蟲有性繁殖階段中的一個(gè)重要角色,。它可以證明新治療方法能夠有效阻止其軌道上的疾病。
咬回去
瘧疾是一種破壞性的全球性疾病,。每年有數(shù)百萬的臨床病例和接近一百萬人死于此病,。瘧疾是由血紅細(xì)胞的感染和被稱為瘧原蟲的一個(gè)微小的寄生蟲而引起的。瘧原蟲有四個(gè)重要物種,。這些生物體由瘧蚊在人與人之間傳播,。當(dāng)瘧蚊叮了一個(gè)受感染人以后，它吮吸血液中含有的寄生蟲,，然后通過叮咬可傳播給下一個(gè)受害者,。
帶領(lǐng)研究學(xué)者并參與諾丁漢大學(xué)生物學(xué)院基因組學(xué)和遺傳學(xué)中心Tewari博士小組的David Guttery博士說：“瘧疾寄生蟲是一個(gè)復(fù)雜的有機(jī)體，了解它是如何繁殖是阻止其傳播疾病的關(guān)鍵,。我們的研究已經(jīng)確認(rèn)了細(xì)胞分裂周期基因在瘧原蟲和它在男性生殖細(xì)胞發(fā)展中的作用,。因此它是阻止瘧原蟲繁殖的“剎車”。 我們發(fā)現(xiàn)如果去除該基因,，雄配子不能形成和分裂出他們的宿主細(xì)胞（稱為exflagellation進(jìn)程）,。阻斷這些細(xì)胞的形成將會(huì)是一個(gè)在預(yù)防瘧疾由蚊子傳播到哺乳動(dòng)物的重要戰(zhàn)略,。”
新目標(biāo)
確認(rèn)的蛋白被稱為CDC20，在伯氏瘧原蟲（在鼠類間傳染）的細(xì)胞分裂周期中發(fā)揮作用,。這種基因顯示在學(xué)多器官的細(xì)胞分裂中都發(fā)揮著重要作用,，但是到目前為止，其在瘧疾寄生蟲上的作用還不得而知,。新的研究對(duì)CDC20在瘧原蟲細(xì)胞分裂和瘧疾寄生蟲雄性細(xì)胞(microgametes)生長(zhǎng)中的作用首次進(jìn)行了描述,。這種雄性細(xì)胞是寄生蟲在人與蚊子之間傳播的基礎(chǔ)?？茖W(xué)家們發(fā)現(xiàn)缺乏這種基因的雄性細(xì)胞將停止迸發(fā)出其宿主細(xì)胞和與雌性細(xì)胞受精,。
瘧疾寄生蟲生命周期中的受精階段發(fā)生在蚊子吮吸感染了瘧疾的血液之后。在此期間,，雄性細(xì)胞前體（小配子體）快速?gòu)?fù)制的DNA產(chǎn)生8個(gè)雄性細(xì)胞（配子）,。這些配子在一個(gè)被稱為exflagellation的過程中衍生出小配子體，并尋找雌性細(xì)胞進(jìn)行受精,。通過阻止exflagellation這個(gè)進(jìn)程,，研究小組確定了一種中斷瘧疾傳播的方法。
這個(gè)研究小組的成員來自諾丁漢大學(xué),，牛津大學(xué),，帝國(guó)理工大學(xué)，萊頓大學(xué),，萊斯特大學(xué)和由MRC資助的國(guó)家醫(yī)學(xué)研究所,，威康信托基金和EviMalar。
諾丁漢大學(xué)的成員在之前的研究中發(fā)現(xiàn)了在瘧疾寄生蟲生命周期中的其他重要因素,。（生物谷Bioon.com）
doi:10.1371/journal.ppat.1002554
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PMID:
A Putative Homologue of CDC20/CDH1 in the Malaria Parasite Is Essential for Male Gamete Development
David S. Guttery1, David J. P. Ferguson2, Benoit Poulin1, Zhengyao Xu1, Ursula Straschil3, Onny Klop4, Lev Solyakov5, Sara M. Sandrini1, Declan Brady1, Conrad A. Nieduszynski1, Chris J. Janse4, Anthony A. Holder6, Andrew B. Tobin5, Rita Tewari1,3*
Cell-cycle progression is governed by a series of essential regulatory proteins. Two major regulators are cell-division cycle protein 20 (CDC20) and its homologue, CDC20 homologue 1 (CDH1), which activate the anaphase-promoting complex/cyclosome (APC/C) in mitosis, and facilitate degradation of mitotic APC/C substrates. The malaria parasite, Plasmodium, is a haploid organism which, during its life-cycle undergoes two stages of mitosis; one associated with asexual multiplication and the other with male gametogenesis. Cell-cycle regulation and DNA replication in Plasmodium was recently shown to be dependent on the activity of a number of protein kinases. However, the function of cell division cycle proteins that are also involved in this process, such as CDC20 and CDH1 is totally unknown. Here we examine the role of a putative CDC20/CDH1 in the rodent malaria Plasmodium berghei (Pb) using reverse genetics. Phylogenetic analysis identified a single putative Plasmodium CDC20/CDH1 homologue (termed CDC20 for simplicity) suggesting that Plasmodium APC/C has only one regulator. In our genetic approach to delete the endogenous cdc20 gene of P. berghei, we demonstrate that PbCDC20 plays a vital role in male gametogenesis, but is not essential for mitosis in the asexual blood stage. Furthermore, qRT-PCR analysis in parasite lines with deletions of two kinase genes involved in male sexual development (map2 and cdpk4), showed a significant increase in cdc20 transcription in activated gametocytes. DNA replication and ultra structural analyses of cdc20 and map2 mutants showed similar blockage of nuclear division at the nuclear spindle/kinetochore stage. CDC20 was phosphorylated in asexual and sexual stages, but the level of modification was higher in activated gametocytes and ookinetes. Changes in global protein phosphorylation patterns in the Δcdc20 mutant parasites were largely different from those observed in the Δmap2 mutant. This suggests that CDC20 and MAP2 are both likely to play independent but vital roles in male gametogenesis.
