Lactate dehydrogenase in Toxoplasma gondii controls virulence, bradyzoite differentiation, and chronic infection.
Lactate dehydrogenase in Toxoplasma gondii controls virulence, bradyzoite differentiation, and chronic infection.
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DOI：
10.1371/journal.pone.0173745
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Igarashi M
中科院分区：
文献类型：
--
作者：
Abdelbaset AE;Fox BA;Karram MH;Abd Ellah MR;Bzik DJ;Igarashi M
在无性生殖阶段，弓形虫阶段在急性期快速复制的速殖子和慢性期缓慢分裂的慢殖子之间转换。相应地，T.弓形虫差异表达乳酸脱氢酶的两种不同基因和同工型，仅在速殖子阶段表达LDH 1，在缓殖子阶段优先表达LDH 2。LDH在厌氧生长条件下催化丙酮酸和乳酸的相互转化，并用于能量供应，然而，LDH 1和LDH 2在无性阶段寄生虫生物学中的确切作用仍不清楚。在这里，我们研究了LDH 1和LDH 2在无性阶段的生物学作用，以及缺失LDH 1、LDH 2或缺失两种基因（Δ ldh 1、Δ ldh 2和Δ ldh 1/2）的缺失突变体的疫苗株潜力。LDH 1的缺失降低了急性寄生虫的毒力，体外缓慢子分化受损，并显着降低体内慢性期囊肿负担。与此相反，LDH 2的缺失损害慢性期囊肿的负担，而不影响毒力或缓殖子分化。LDH 1和LDH 2的缺失在慢性期囊肿负荷中引起更严重的缺陷。这些LDH突变表型与任何生长缺陷无关。用低剂量的LDH缺失突变体疫苗接种小鼠引起对致死性攻击感染的有效保护性免疫，证明LDH缺失突变体的疫苗潜力。这些结果提示T.弓形虫控制毒力、缓殖子分化和慢性感染，并揭示LDH突变体作为疫苗株的潜力。
In the asexual stages, Toxoplasma gondii stage converts between acute phase rapidly replicating tachyzoites and chronic phase slowly dividing bradyzoites. Correspondingly, T. gondii differentially expresses two distinct genes and isoforms of the lactate dehydrogenase enzyme, expressing LDH1 exclusively in the tachyzoite stage and LDH2 preferentially in the bradyzoite stage. LDH catalyzes the interconversion of pyruvate and lactate in anaerobic growth conditions and is utilized for energy supply, however, the precise role of LDH1 and LDH2 in parasite biology in the asexual stages is still unclear. Here, we investigated the biological role of LDH1 and LDH2 in the asexual stages, and the vaccine strain potential of deletion mutants lacking LDH1, LDH2, or both genes (Δldh1, Δldh2 and Δldh1/2). Deletion of LDH1 reduced acute parasite virulence, impaired bradyzoite differentiation in vitro, and markedly reduced chronic stage cyst burdens in vivo. In contrast, deletion of LDH2 impaired chronic stage cyst burdens without affecting virulence or bradyzoite differentiation. Deletion of both LDH1 and LDH2 induced a more severe defect in chronic stage cyst burdens. These LDH mutant phenotypes were not associated with any growth defect. Vaccination of mice with a low dose of mutants deleted for LDH elicited effective protective immunity to lethal challenge infection, demonstrating the vaccine potential of LDH deletion mutants. These results suggest that lactate dehydrogenase in T. gondii controls virulence, bradyzoite differentiation, and chronic infection and reveals the potential of LDH mutants as vaccine strains.