A Lactate Fermentation Mutant of Toxoplasma Stimulates Protective Immunity Against Acute and Chronic Toxoplasmosis.
A Lactate Fermentation Mutant of Toxoplasma Stimulates Protective Immunity Against Acute and Chronic Toxoplasmosis.
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弓形虫的乳酸发酵突变体可刺激针对急性和慢性弓形虫病的保护性免疫力。
DOI：
10.3389/fimmu.2018.01814
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发表时间：
2018
影响因子：
7.3
通讯作者：
Shen B
中科院分区：
文献类型：
--
作者：
Xia N;Zhou T;Liang X;Ye S;Zhao P;Yang J;Zhou Y;Zhao J;Shen B
弓形虫是一种重要的人畜共患病病原体，感染着世界三分之一的人口和众多的动物，造成巨大的医疗负担和社会经济问题。接种疫苗是降低全球血清流行率的有效途径，然而，目前还没有理想的疫苗。我们最近发现，缺乏乳酸脱氢酶ldh1和ldh2的弓形虫突变体(Δldh)在体外生长良好，但不能在小鼠体内繁殖，使其成为一种很好的活疫苗候选。在这里，我们用小鼠模型测试了ME49Δ乳酸脱氢酶的保护效果。免疫小鼠可有效抵抗多种野生型毒株的致死攻击，包括1型RH株、2型毒株ME49、3型毒株VEG和中国1号野毒株。大多数情况下，单次免疫的保护率接近100%，对速殖子和组织包囊的攻击都有很好的效果。再次挑战的寄生虫无法在接种疫苗的小鼠中繁殖，也不会形成组织包囊。弓形虫特异性免疫球蛋白在免疫后30 天产生较高水平，并在整个试验期间保持较高水平(至少12 5 天)。然而，用免疫小鼠的血清被动免疫幼稚小鼠确实减少了寄生虫的繁殖，但对寄生虫感染的整体保护相当有限。另一方面，Th1型细胞因子如Δ-γ和IL-12在免疫早期水平升高。此外，从免疫小鼠中提取的脾细胞能够在弓形虫抗原刺激下快速而强劲地诱导干扰素-γ和其他促炎细胞因子的产生。综上所述，细胞免疫应答是Δ乳酸脱氢酶疫苗诱导保护性免疫的主要因素，体液免疫也起一定作用。我们还在ME49中产生了尿嘧啶营养缺陷型突变体，并比较了它们与Δ乳酸脱氢酶突变体的免疫保护效率。结果表明，这两种类型的突变体与活疫苗候选株具有相似的特性。综上所述，这些结果表明，缺乏LDH的突变体毒力严重减弱，但能够诱导强烈的抗弓形虫免疫反应，因此是很好的活疫苗候选者。
Toxoplasma gondii is an important zoonotic pathogen infecting one-third of the world’s population and numerous animals, causing significant healthcare burden and socioeconomic problems. Vaccination is an efficient way to reduce global sero-prevalence, however, ideal vaccines are not yet available. We recently discovered that the Toxoplasma mutant lacking both lactate dehydrogenases LDH1 and LDH2 (Δldh) grew well in vitro but was unable to propagate in mice, making it a good live vaccine candidate. Here, we tested the protection efficacy of ME49 Δldh using a mouse model. Vaccinated mice were efficiently protected from the lethal challenge of a variety of wild-type strains, including type 1 strain RH, type 2 strain ME49, type 3 strain VEG, and a field isolate of Chinese 1. The protection efficacies of a single vaccination were nearly 100% for most cases and it worked well against the challenges of both tachyzoites and tissue cysts. Re-challenging parasites were unable to propagate in vaccinated mice, nor did they make tissue cysts. High levels of Toxoplasma-specific IgG were produced 30 days after immunization and stayed high during the whole tests (at least 125 days). However, passive immunization of naïve mice with sera from vaccinated mice did reduce parasite propagation, but the overall protection against parasite infections was rather limited. On the other hand, Δldh immunization evoked elevated levels of Th1 cytokines like INF-γ and IL-12, at early time points. In addition, splenocytes extracted from immunized mice were able to induce quick and robust INF-γ and other pro-inflammatory cytokine production upon T. gondii antigen stimulation. Together these results suggest that cellular immune responses are the main contributors to the protective immunity elicited by Δldh vaccination, and humoral immunity also contributes partially. We also generated uracil auxotrophic mutants in ME49 and compared their immune protection efficiencies to the Δldh mutants. The results showed that these two types of mutants have similar properties as live vaccine candidates. Taken together, these results suggest that mutants lacking LDH were severely attenuated in virulence but were able to induce strong anti-toxoplasma immune responses, therefore are good candidates for live vaccines.
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影响因子：
3.1
作者：
Saeij, JPJ;Boyle, JP;Boothroyd, JC
通讯作者：
Boothroyd, JC
弓形虫病发育中的药物：进步，挑战和当前状态。
DOI：
10.2147/dddt.s60973
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Alday PH;Doggett JS
通讯作者：
Doggett JS
影响因子：
4
作者：
Dubey, JP
通讯作者：
Dubey, JP
影响因子：
2.4
作者：
BUXTON, D;INNES, EA
通讯作者：
INNES, EA
影响因子：
6.4
作者：
Beghetto, E;Nielsen, HV;Gargano, N
通讯作者：
Gargano, N