Miyahira Y, García-Sastre A, Rodriguez D, Rodriguez J R, Murata K, Tsuji M, Palese P, Esteban M, Zavala F, Nussenzweig R S
Department of Medical and Molecular Parasitology, New York University Medical Center, 341 E. 25th Street, New York, NY 10010, USA.
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3954-9. doi: 10.1073/pnas.95.7.3954.
Extensive studies on protective immunity to rodent malaria provided the basis for the current experiments in which mice were immunized with recombinant (re) influenza and vaccinia viruses expressing selected sequences of the circumsporozoite (CS) protein of the human malaria parasite Plasmodium falciparum. Mice of different H-2 haplotypes immunized with re influenza viruses expressing the immunodominant B cell epitope of this CS protein produced high titers of antibodies to the parasite. A cytotoxic T lymphocyte epitope of the CS protein of P. falciparum, PF3, recognized by CD8+ T cells of H-2(k) mice, was expressed in a re vaccinia virus (VacPf) and a re influenza virus (FluPf). Immunization of mice with either FluPf or VacPf elicited a modest CS-specific CD8+ T cell response detected by interferon gamma secretion of individual immune cells. Priming of mice with FluPf, followed by a booster with VacPf, resulted in a striking enhancement of this T cell response. The reverse protocol, i.e., priming with VacPf followed by a booster with FluPf, failed to enhance the primary response. VacPf also greatly enhanced the primary response of mice injected with P. falciparum sporozoites or with a lipopeptide containing PF3. A booster with FluPf also amplified the response of lipopeptide- or sporozoite-primed mice but less than a VacPf booster did. Although mice are not susceptible to infection by P. falciparum sporozoites, we demonstrated that administration of two distinct immunogens expressing PF3 elicited activated, extravasating CS-specific T cells that protected against an intracerebral VacPf challenge.
对啮齿动物疟疾保护性免疫的广泛研究为当前实验提供了基础。在这些实验中，用表达人类疟原虫恶性疟原虫环子孢子（CS）蛋白选定序列的重组流感病毒和痘苗病毒对小鼠进行免疫。用表达该CS蛋白免疫显性B细胞表位的重组流感病毒免疫不同H-2单倍型的小鼠，可产生高滴度的针对该寄生虫的抗体。恶性疟原虫CS蛋白的一个细胞毒性T淋巴细胞表位PF3，可被H-2(k)小鼠的CD8+ T细胞识别，在重组痘苗病毒（VacPf）和重组流感病毒（FluPf）中表达。用FluPf或VacPf免疫小鼠，通过单个免疫细胞分泌干扰素γ检测到适度的CS特异性CD8+ T细胞反应。先用FluPf对小鼠进行初免，然后用VacPf进行加强免疫，导致该T细胞反应显著增强。相反的方案，即用VacPf进行初免，然后用FluPf进行加强免疫，未能增强初次反应。VacPf还极大地增强了注射恶性疟原虫子孢子或含PF3脂肽的小鼠的初次反应。用FluPf进行加强免疫也增强了脂肽或子孢子初免小鼠的反应，但不如VacPf加强免疫增强的效果好。虽然小鼠对恶性疟原虫子孢子感染不敏感，但我们证明，给予两种表达PF3的不同免疫原可引发活化的、渗出的CS特异性T细胞，这些T细胞可保护小鼠免受脑内VacPf攻击。
