Sahu Tejram, Lambert Lynn, Herrod Jessica, Conteh Solomon, Orr-Gonzalez Sachy, Carter Dariyen, Duffy Patrick E
Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville MD, USA.
Front Microbiol. 2015 Apr 9;6:283. doi: 10.3389/fmicb.2015.00283. eCollection 2015.
Chemoprophylaxis Vaccination (CVac) confers long lasting sterile protection against homologous parasite strains in humans, and involves inoculation of infectious sporozoites (SPZ) under drug cover. CVac using the drug chloroquine (CQ) induces pre-erythrocytic immunity in humans that includes antibody to SPZ and T-cell responses to liver stage (LS) parasites. The mechanism by which CVac with CQ induces strong protective immunity is not understood as untreated infections do not confer protection. CQ kills blood stage parasites, but its effect on LS parasites is poorly studied. Here we hypothesized that CQ may prolong or perturb LS development of Plasmodium, as a potential explanation for enhanced pre-erythrocytic immune responses. Balb/c mice with or without CQ prophylaxis were infected with sporozoite forms of a luciferase-expressing rodent parasite, Plasmodium yoelii-Luc (Py-Luc). Mice that received primaquine, a drug that kills LS parasites, served as a positive control of drug effect. Parasite burden in liver was measured both by bioluminescence and by qRT-PCR quantification of parasite transcript. Time to appearance of parasites in the blood was monitored by microscopic analysis of Giemsa-stained thick and thin blood smears. The parasite load in livers of CQ-treated and untreated mice did not significantly differ at any of the time points studied. Parasites appeared in the blood smears of both CQ-treated and untreated mice 3 days after infection. Taken together, our findings confirm that CQ neither eliminates LS parasites nor delays their development. Further investigations into the mechanism of CQ-induced protection after CVac are required, and may give insights relevant to drug and vaccine development.
化学预防接种疫苗（CVac）可对人类同源寄生虫菌株提供持久的无菌保护，且涉及在药物掩护下接种感染性子孢子（SPZ）。使用氯喹（CQ）的CVac可在人类中诱导红细胞前期免疫，其中包括针对SPZ的抗体以及对肝期（LS）寄生虫的T细胞反应。使用CQ的CVac诱导强大保护性免疫的机制尚不清楚，因为未经治疗的感染无法提供保护。CQ可杀死血期寄生虫，但其对LS寄生虫的影响研究较少。在此，我们假设CQ可能会延长或干扰疟原虫的LS发育，这可能是红细胞前期免疫反应增强的一个潜在解释。对有或没有CQ预防的Balb/c小鼠接种表达荧光素酶的啮齿动物疟原虫约氏疟原虫-Luc（Py-Luc）的子孢子形式。接受伯氨喹（一种可杀死LS寄生虫的药物）的小鼠用作药物效果的阳性对照。通过生物发光以及通过对寄生虫转录本进行qRT-PCR定量来测量肝脏中的寄生虫负荷。通过对吉姆萨染色的厚血涂片和薄血涂片进行显微镜分析来监测血液中出现寄生虫的时间。在研究的任何时间点，接受CQ治疗和未接受治疗的小鼠肝脏中的寄生虫负荷均无显著差异。感染后3天，CQ治疗组和未治疗组小鼠的血涂片中均出现了寄生虫。综上所述，我们的研究结果证实，CQ既不能消除LS寄生虫，也不会延迟其发育。需要进一步研究CVac后CQ诱导保护的机制，这可能会为药物和疫苗开发提供相关见解。
