The TLR2/6 ligand PAM2CSK4 is a Th2 polarizing adjuvant in Leishmania major and Brugia malayi murine vaccine models.
The TLR2/6 ligand PAM2CSK4 is a Th2 polarizing adjuvant in Leishmania major and Brugia malayi murine vaccine models.
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DOI：
10.1186/s13071-016-1381-0
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发表时间：
2016-02-20
影响因子：
3.2
通讯作者：
Taylor MJ
中科院分区：
文献类型：
--
作者：
Halliday A;Turner JD;Guimarães A;Bates PA;Taylor MJ
Toll样受体（TLR）在针对病原体的先天性和适应性免疫反应中发挥重要作用，并且是新型疫苗佐剂的靶点。TLR 2在皮肤利什曼病感染期间的寄生虫识别和免疫应答激活中起作用，这表明TLR 2可以被佐剂靶向用于利什曼病疫苗。因此，我们探索了在寄生虫感染的疫苗模型中使用分别激活TLR 2/6和TLR 2/1异二聚体的Pam 2CSK 4（Pam 2）和Pam 3CSK 4（Pam 3）脂肽佐剂。使用两种疫苗模型探索脂肽佐剂的使用。对于皮肤利什曼病，将脂肽佐剂Pam 2和Pam 3与Th 1驱动的双链DNA TLR 9激动剂CpG的脂肽佐剂进行比较，以了解它们提高高压灭菌的硕大利什曼原虫（ALM）疫苗保护免受利什曼原虫的效力的能力。严重感染还在B的腹膜感染模型中评估了Pam 2增强可溶性马来丝虫微丝蚴提取物（BmMfE）疫苗预防丝虫感染的效力的能力。马来丝虫病攻击后评估寄生虫抗原特异性细胞和体液免疫应答。在含ALM的疫苗中使用脂肽对感染L. major，而Pam 2加重了攻击后接种疫苗的小鼠的疾病严重程度。Pam 2和较小程度的Pam 3能够在该模型中提高攻击后的抗原特异性免疫应答，但这些应答显示出偏斜的Th 2表型，其特征在于IgG 1水平升高。在B。在马来疫苗模型中，使用Pam 2作为佐剂与BmMfE诱导显著的保护性免疫，其水平与包含明矾佐剂的水平相同。在此，发现Pam 2和明矾都增强了攻击后抗原特异性抗体的产生，并且Pam 2显著提高了脾细胞产生的抗原特异性IL-4、IL-5和IL-13的水平。这些数据表明，TLR 2/6靶向配体可以被认为是需要强大的Th 2和/或抗体依赖性免疫的疫苗的佐剂。
Toll-like receptors (TLRs) play an important role in the innate and adaptive immune responses to pathogens, and are the target of new vaccine adjuvants. TLR2 plays a role in parasite recognition and activation of immune responses during cutaneous leishmaniasis infection, suggesting that TLR2 could be targeted by adjuvants for use in Leishmania vaccines. We therefore explored using Pam2CSK4 (Pam2) and Pam3CSK4 (Pam3) lipopeptide adjuvants, which activate TLR2/6 and TLR2/1 heterodimers respectively, in vaccine models for parasitic infections. The use of lipopeptide adjuvants was explored using two vaccine models. For cutaneous leishmaniasis, the lipopeptide adjuvants Pam2 and Pam3 were compared to that of the Th1-driving double-stranded DNA TLR9 agonist CpG for their ability to improve the efficacy of the autoclaved Leishmania major (ALM) vaccine to protect against L. major infection. The ability of Pam2 to enhance the efficacy of a soluble Brugia malayi microfilariae extract (BmMfE) vaccine to protect against filarial infection was also assessed in a peritoneal infection model of B. malayi filariasis. Parasite antigen-specific cellular and humoral immune responses were assessed post-challenge. The use of lipopeptides in ALM-containing vaccines did not provide any protection upon infection with L. major, and Pam2 exacerbated the disease severity in vaccinated mice post-challenge. Pam2, and to a lesser extent Pam3, were able to elevate antigen-specific immune responses post-challenge in this model, but these responses displayed a skewed Th2 phenotype as characterised by elevated levels of IgG1. In the B. malayi vaccine model, the use of Pam2 as an adjuvant with BmMfE induced significant protective immunity to the same level as inclusion of an Alum adjuvant. Here, both Pam2 and Alum were found to enhance antigen-specific antibody production post-challenge, and Pam2 significantly elevated levels of antigen-specific IL-4, IL-5 and IL-13 produced by splenocytes. These data indicate that TLR2/6-targeting ligands could be considered as adjuvants for vaccines that require robust Th2 and/or antibody-dependent immunity.