The Impact of BKI-1294 Therapy in Mice Infected With the Apicomplexan Parasite Neospora caninum and Re-infected During Pregnancy.
The Impact of BKI-1294 Therapy in Mice Infected With the Apicomplexan Parasite Neospora caninum and Re-infected During Pregnancy.
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DOI：
10.3389/fvets.2020.587570
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发表时间：
2020
影响因子：
3.2
通讯作者：
Hemphill A
中科院分区：
文献类型：
--
作者：
Winzer P;Imhof D;Anghel N;Ritler D;Müller J;Boubaker G;Aguado-Martinez A;Ortega-Mora LM;Ojo KK;VanVoorhis WC;Hemphill A
犬新孢子虫速殖子体外暴露于BKI-1294导致形成长寿命多核复合物（MNC）。然而，在N.怀孕期间的犬感染是安全的，并大大降低了幼崽死亡率和垂直传播。我们假设，MNC的形成可能引发有助于BKI体内疗效的免疫应答。在这项研究中，小鼠首先接种亚致死剂量的N。犬速殖子，并用BKI-1294处理。然后，我们研究了这些治疗后交配和怀孕期间再次感染的影响。评价了对生育力、幼仔存活率、垂直传播和母体寄生虫负荷的影响。通过ELISA或Luminex™ 200系统评估血清或脾细胞培养上清液中的细胞因子，并通过ELISA、蛋白质印迹和免疫蛋白质组学比较针对速殖子和MNC抗原的体液免疫应答。我们的研究结果表明，BKI-1294处理活疫苗接种小鼠降低了母鼠脑寄生虫负荷，但导致新生幼仔死亡率和垂直传播较高。在活疫苗接种的小鼠中，与未处理的小鼠相比，BKI-1294处理的动物中的细胞因子水平（最显著的是IFN-γ、IL-10和IL-12）始终较低。此外，比较性蛋白质印迹法在MNC提取物中鉴定了两条蛋白质条带，这两条蛋白质条带仅被BKI-1294处理的活疫苗接种小鼠的血清识别，而在速殖子提取物中未发现。我们得出结论，用BKI-1294处理活疫苗接种小鼠影响了抗感染的细胞和体液免疫应答，影响了活疫苗的安全性，并降低了对妊娠期间再感染和垂直传播的保护。
Exposure of Neospora caninum tachyzoites to BKI-1294 in vitro results in the formation of long-lived multinucleated complexes (MNCs). However, in vivo treatment of BALB/c mice with BKI-1294 shortly after N. caninum infection during pregnancy was safe and profoundly reduced pup mortality and vertical transmission. We hypothesized that the formation of MNCs could trigger immune responses that contribute to BKI efficacy in vivo. In this study, mice were first vaccinated with a sublethal dose of N. caninum tachyzoites and were treated with BKI-1294. We then investigated the effects of these treatments after mating and re-infection during pregnancy. Effects on fertility, pup survival, vertical transmission, and parasite load in dams were evaluated. Cytokines in sera or splenocyte culture supernatants were assessed by either ELISA or the Luminex™ 200 system, and humoral immune responses against tachyzoite and MNC antigens were compared by ELISA, Western blotting and immunoproteomics. Our results showed that BKI-1294 treatment of live-vaccinated mice reduced the cerebral parasite load in the dams, but resulted in higher neonatal pup mortality and vertical transmission. In live-vaccinated mice, cytokine levels, most notably IFN-y, IL-10, and IL-12, were consistently lower in BKI-1294 treated animals compared to non-treated mice. In addition, comparative Western blotting identified two protein bands in MNC extracts that were only recognized by sera of live-vaccinated mice treated with BKI-1294, and were not found in tachyzoite extracts. We conclude that treatment of live-vaccinated mice with BKI-1294 influenced the cellular and humoral immune responses against infection, affected the safety of the live-vaccine, and decreased protection against re-infection and vertical transmission during pregnancy.
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影响因子：
4
作者：
Lim DC;Cooke BM;Doerig C;Saeij JP
通讯作者：
Saeij JP
影响因子：
2.4
作者：
Dellarupe, Andrea;Regidor-Cerrillo, Javier;Ortega-Mora, Luis M.
通讯作者：
Ortega-Mora, Luis M.
影响因子：
1.3
作者：
Lindsay, DS;Lenz, SD;Brake, DA
通讯作者：
Brake, DA
影响因子：
5.5
作者：
Marugan-Hernandez, V.;Ortega-Mora, L. M.;Alvarez-Garcia, G.
通讯作者：
Alvarez-Garcia, G.
影响因子：
30.3
作者：
Billker O;Lourido S;Sibley LD
通讯作者：
Sibley LD