A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites.
A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites.
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DOI：
10.1371/journal.ppat.1003331
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Boothroyd JC
中科院分区：
文献类型：
--
作者：
Caffaro CE;Koshy AA;Liu L;Zeiner GM;Hirschberg CB;Boothroyd JC
刚地弓形虫是一种细胞内寄生虫，在中间宿主体内由急性感染转变为慢性感染状态，这使得弓形虫能够逃避免疫检测和清除。人们普遍认为，组织囊肿的周缘是高度和特异性地修饰多糖修饰的；然而，这些修饰在慢性感染的建立和持续中的作用尚未被调查。在这里，我们鉴定和生化和生物学表征弓形虫核苷酸糖转运蛋白（TgNST1），这是必需的囊壁糖基化。TgNST1基因缺失的弓形虫菌株（Δnst1）在体外形成囊状结构，但不再与凝集素相互作用，这表明Δnst1菌株缺乏运输和使用糖来生物合成囊壁结构。体内感染实验表明，缺乏TgNST1活性不会明显影响感染的急性（速殖子）阶段或寄生虫对大脑的趋向性，但Δnst1寄生虫在感染的慢性阶段存在严重的持久性缺陷。这些结果首次证明了寄生虫糖结合物在弓形虫组织囊肿持续存在中的关键作用。弓形虫组织囊肿在免疫能力强的宿主慢性感染期间对寄生虫的持续存在至关重要。虽然已经做出了巨大的努力来确定触发和维持寄生虫寄生的分子因素，但装饰囊肿壁的糖缀合物的作用却很少受到关注。在这里，我们鉴定并表征了一个真正的核苷酸-糖转运蛋白TgNST1，其活性是囊壁糖缀合物的适当组装所必需的。我们发现TgNST1的缺失在感染的速殖子和慢殖子阶段都会干扰糖基化，并且我们观察到Δnst1寄生虫维持慢性感染的能力存在实质性缺陷。令人惊讶的是，Δnst1寄生虫在小鼠急性感染中没有明显缺陷，并且显示出野生型水平和迁移到大脑的速度。这些结果强调了囊壁糖基化在慢性感染期间寄生虫持续存在中的重要作用，并提示靶向核苷酸-糖转运体和糖基化所需的其他酶的药物，可能与靶向其他途径的药物联合使用，可能有助于预防慢性寄生虫感染的建立。
Toxoplasma gondii is an intracellular parasite that transitions from acute infection to a chronic infective state in its intermediate host via encystation, which enables the parasite to evade immune detection and clearance. It is widely accepted that the tissue cyst perimeter is highly and specifically decorated with glycan modifications; however, the role of these modifications in the establishment and persistence of chronic infection has not been investigated. Here we identify and biochemically and biologically characterize a Toxoplasma nucleotide-sugar transporter (TgNST1) that is required for cyst wall glycosylation. Toxoplasma strains deleted for the TgNST1 gene (Δnst1) form cyst-like structures in vitro but no longer interact with lectins, suggesting that Δnst1 strains are deficient in the transport and use of sugars for the biosynthesis of cyst-wall structures. In vivo infection experiments demonstrate that the lack of TgNST1 activity does not detectably impact the acute (tachyzoite) stages of an infection or tropism of the parasite for the brain but that Δnst1 parasites are severely defective in persistence during the chronic stages of the infection. These results demonstrate for the first time the critical role of parasite glycoconjugates in the persistence of Toxoplasma tissue cysts. The Toxoplasma tissue cyst is essential to the persistence of the parasite during the chronic infection of an immunocompetent host. While significant efforts have been made to identify molecular factors that trigger and sustain parasite encystation, the role of the glycoconjugates that decorate the cyst wall has received little attention. Here we identify and characterize a bona fide nucleotide-sugar transporter, TgNST1, whose activity is required for the proper assembly of cyst wall glycoconjugates. We found that deletion of TgNST1 interferes with glycosylation during both the tachyzoite and bradyzoite stages of infection, and we observed substantial defects in the ability of Δnst1 parasites to maintain chronic infection. Surprisingly, Δnst1 parasites were not significantly defective in acute infection of mice, and showed wild type levels and migration rates to the brain. These results highlight the important role of cyst-wall glycosylation in parasite persistence during chronic infection, and suggest that drugs targeting nucleotide-sugar transporters and other enzymes required for glycosylation, perhaps in combination with drugs targeting other pathways, might be useful to prevent the establishment of chronic parasite infection.
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DOI：
10.1073/pnas.0608159103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Caffaro, Carolina E.;Hirschberg, Carlos B.;Berninsone, Patricia M.
通讯作者：
Berninsone, Patricia M.
影响因子：
3.1
作者：
Tobin, Crystal M.;Knoll, Laura J.
通讯作者：
Knoll, Laura J.
影响因子：
4
作者：
Dubey, JP
通讯作者：
Dubey, JP
影响因子：
2.9
作者：
Garenaux, Estelle;Shams-Eldin, Hosam;Schwarz, Ralph T.
通讯作者：
Schwarz, Ralph T.
影响因子：
4
作者：
Azzouz, N;Rauscher, B;Schwarz, RT
通讯作者：
Schwarz, RT