Julia M Sattler, Lukas Keiber, Aiman Abdelrahim, Xinyu Zheng, Martin Jäcklin, Luisa Zechel, Catherine A Moreau, Smilla Steinbrück, Manuel Fischer, Chris J Janse, Angelika Hoffmann, Franziska Hentzschel, Friedrich Frischknecht
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引用次数: 0
摘要
目前正在探索利用疟原虫活体接种疟疾疫苗的方法,即利用减毒的蚊源性孢子虫或减毒的血期寄生虫。这两种方法都将得益于可获得血期繁殖率降低的减毒和无毒寄生虫。在这里,我们筛选了生长缓慢的啮齿类寄生虫 P. berghei 和人类寄生虫 P. falciparum 的基因缺失突变体。此外,我们还测试了伯格希氏疟原虫突变体的无毒性和解决血期感染的能力,同时保留了孢子虫的形成和肝脏感染。以 51 个基因为靶标,产生了 18 个伯格氏疟原虫基因缺失突变体,其中几个突变体可引起轻度感染。两种最弱的突变体的血液阶段感染或孢子虫感染都能被免疫反应清除。对小鼠进行免疫可使其在受到野生型孢子虫挑战后免于发病。六种恶性疟原虫基因缺失突变体中有两种生长速度缓慢。生长缓慢、无毒的恶性疟原虫突变体将成为诱导免疫反应的宝贵工具,有助于开发新的寄生虫减毒疫苗并保护现有疫苗。
Experimental vaccination by single dose sporozoite injection of blood-stage attenuated malaria parasites.
Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.
期刊介绍:
EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance.
To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields:
Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention).
Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease.
Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)