Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Pathology, Ohio State University, Columbus, Ohio, United States of America.
PLoS Negl Trop Dis. 2014 Jun 19;8(6):e2951. doi: 10.1371/journal.pntd.0002951. eCollection 2014 Jun.
Visceral leishmaniasis is the most clinically relevant and dangerous form of human leishmaniasis. Most traditional drugs for treatment of leishmaniasis are toxic, possess many adverse reactions and drug resistance is emerging. Therefore, there is urgent need for identification of new therapeutic targets. Recently, we found that mice with an inactivating knock-in mutation in the p110δ isoform of pi3k, (p110δ(d910a)) are hyper resistant to L. major, develop minimal cutaneous lesion and rapidly clear their parasite. Here, we investigated whether pi3k signaling also regulates resistance to L. donovani, one of the causative agents of visceral leishmaniasis.
METHODOLOGY/PRINCIPAL FINDINGS: WT and p110δ(D910A) mice (on a BALB/c background) were infected with L. donovani. At different time points, parasite burden and granuloma formation were assessed. T and B cell responses in the liver and spleen were determined. In addition, Tregs were expanded in vivo and its impact on resistance was assessed. We found that p110δ(D910A) mice had significantly reduced splenomegaly and hepatomegaly and these organs harbored significantly fewer parasites than those of WT mice. Interestingly, infected p110δ(D910A) mice liver contains fewer and less organized granulomas than their infected WT counterparts. Cells from p110δ(D910A) mice were significantly impaired in their ability to produce cytokines compared to WT mice. The percentage and absolute numbers of Tregs in infected p110δ(D910A) mice were lower than those in WT mice throughout the course of infection. In vivo expansion of Tregs in infected p110δ(D910A) mice abolished their enhanced resistance to L. donovani infection.
CONCLUSIONS/SIGNIFICANCE: Our results indicate that the enhanced resistance of p110δ(D910A) mice to L. donovani infection is due to impaired activities of Tregs. They further show that resistance to Leishmania in the absence of p110δ signaling is independent of parasite species, suggesting that targeting the PI3K signaling pathway may be useful for treatment of both visceral and cutaneous leishmaniasis.
内脏利什曼病是最具临床相关性和危险性的人类利什曼病形式。大多数用于治疗利什曼病的传统药物都具有毒性，存在许多不良反应，而且耐药性正在出现。因此，迫切需要确定新的治疗靶点。最近，我们发现 p110δ 同工型 pi3k 的失活敲入突变（p110δ(d910a)）的小鼠对 L. major 具有高抗性，皮肤损伤最小，寄生虫迅速清除。在这里，我们研究了 pi3k 信号是否也调节对内脏利什曼病的一种病原体 L. donovani 的抗性。
方法/主要发现：WT 和 p110δ(D910A) 小鼠（在 BALB/c 背景下）感染 L. donovani。在不同时间点，评估寄生虫负荷和肉芽肿形成。测定肝脏和脾脏中的 T 和 B 细胞反应。此外，体内扩增 Tregs 并评估其对抗性的影响。我们发现 p110δ(D910A) 小鼠的脾肿大和肝肿大明显减少，这些器官中的寄生虫数量明显少于 WT 小鼠。有趣的是，感染 p110δ(D910A) 小鼠的肝脏中的肉芽肿数量更少且组织更不完整。与 WT 小鼠相比，p110δ(D910A) 小鼠的细胞产生细胞因子的能力显著受损。感染 p110δ(D910A) 小鼠的 Tregs 的百分比和绝对数量在整个感染过程中均低于 WT 小鼠。在感染 p110δ(D910A) 小鼠体内扩增 Tregs 可消除其对 L. donovani 感染的增强抗性。
结论/意义：我们的结果表明，p110δ(D910A) 小鼠对 L. donovani 感染的增强抗性是由于 Tregs 活性受损所致。它们进一步表明，在没有 p110δ 信号的情况下对利什曼原虫的抗性与寄生虫种类无关，这表明靶向 PI3K 信号通路可能对治疗内脏和皮肤利什曼病都有用。
