Reiman Jennifer M, Kumar Sanjai, Rodriguez Ingrid B, Gnidehou Sedami, Ito Koichi, Stanisic Danielle I, Lee Moses, McPhun Virginia, Majam Victoria, Willemsen Nicole M, Batzloff Michael R, Raja Amber I, Dooley Brad, Hoffman Stephen L, Yanow Stephanie K, Good Michael F
Institute for Glycomics Griffith University Gold Coast QLD Australia.
Laboratory of Emerging Pathogens Division of Emerging and Transfusion Transmitted Diseases CBER, FDA Rockville MD USA.
Clin Transl Immunology. 2018 Apr 11;7(4):e1015. doi: 10.1002/cti2.1015. eCollection 2018.
Blood stage malaria parasites attenuated with seco-cyclopropyl pyrrolo indole (CPI) analogues induce robust immunity in mice to homologous and heterologous malaria parasites and are being considered for the development of a human vaccine. However, it is not understood how attenuated parasites induce immunity. We showed that following vaccination, parasite DNA persisted in blood for several months, raising the possibility that ongoing immune stimulation may be critical. However, parasites were not seen microscopically beyond 24 h postvaccination. We aimed to provide a mechanistic understanding of immune induction.
Mice were vaccinated with chemically attenuated parasites. PCR and adoptive transfer studies were used to determine the presence of parasites and antigen . In other experiments, parasitised red blood cells were attenuated and RNA and antigen expression studied.
We show that blood transferred from vaccinated mice into naïve mice activates T cells and induces complete protective immunity in the recipient mice strongly suggesting that there is persistence of parasite antigen postvaccination. This is supported by the presence of parasite RNA in vaccinated mice and both RNA and antigen expression in cultures treated with CPI drugs . In addition, drugs that block parasite growth also prevent the induction of immunity in vaccinated mice, indicating that some growth of attenuated parasites is required for immune induction.
Attenuated parasites persist at submicroscopic levels in the blood of mice postvaccination with the ability to activate T cells and induce ongoing protective immune responses.
用开环环丙基吡咯吲哚（CPI）类似物减毒的血液期疟原虫可在小鼠体内诱导针对同源和异源疟原虫的强大免疫力，目前正考虑将其用于开发人类疫苗。然而，尚不清楚减毒疟原虫是如何诱导免疫的。我们发现，接种疫苗后，疟原虫DNA在血液中持续存在数月，这增加了持续免疫刺激可能至关重要的可能性。然而，接种疫苗后24小时后在显微镜下就看不到疟原虫了。我们旨在对免疫诱导提供一个机制性的理解。
用化学减毒的疟原虫给小鼠接种疫苗。采用PCR和过继转移研究来确定疟原虫和抗原的存在。在其他实验中，对感染疟原虫的红细胞进行减毒，并研究RNA和抗原表达。
我们发现，将接种疫苗小鼠的血液转移到未接种疫苗的小鼠体内可激活T细胞，并在受体小鼠中诱导完全的保护性免疫，这强烈表明接种疫苗后疟原虫抗原持续存在。接种疫苗小鼠中疟原虫RNA的存在以及用CPI药物处理的培养物中RNA和抗原的表达均支持这一点。此外，阻断疟原虫生长的药物也可防止接种疫苗小鼠诱导免疫，这表明减毒疟原虫的一些生长对于免疫诱导是必需的。
接种疫苗后，减毒疟原虫以亚显微水平持续存在于小鼠血液中，具有激活T细胞并诱导持续保护性免疫反应的能力。
