Kedzierski L, Curtis J M, Kedzierska K
Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville 3052, Australia.
Parasitology. 2009 Jul;136(8):833-40. doi: 10.1017/S0031182009006301. Epub 2009 Jun 2.
Vaccination remains the best hope for control of all forms of leishmaniasis, and the development of a safe and effective vaccine is a critical global public-health priority. Our previous work showed that immunization with non-persistent phosphomannomutase-deficient (DeltaPMM) Leishmania major parasites confers significant protection in susceptible BALB/c mice due to increased T-cell numbers and suppression of IL-10 and IL-13 early during infection. Here, we complemented the DeltaPMM L. major parasites with human PMM2 to determine whether we could further improve the protection. Complemented DeltaPMM parasites have restored glycoconjugate biosynthesis, while retaining avirulence of the parental knockout strain. Immunization with hPMM2 add-back parasites showed similar Th1/Th2 cytokine profiles to that observed in DeltaPMM-vaccinated mice. However, the numbers of the activated CD4+CD44(hi) and CD8+CD44(hi) T cells recruited to the draining lymph nodes early after Leishmania infection were reduced, leading to decreased protection following hPMM2-immunization. Thus, the magnitude of T-cell responses early in the infection and the absence of mannose-rich glycoconjugates determine the protective outcome of anti-leishmanial immunity.
接种疫苗仍然是控制各种利什曼病的最大希望,开发一种安全有效的疫苗是一项至关重要的全球公共卫生优先事项。我们之前的研究表明,用非持久性磷酸甘露糖变位酶缺陷型(DeltaPMM)的硕大利什曼原虫寄生虫进行免疫接种,可在易感的BALB/c小鼠中提供显著保护,这是由于感染早期T细胞数量增加以及IL-10和IL-13受到抑制。在此,我们用人PMM2对DeltaPMM硕大利什曼原虫寄生虫进行互补,以确定是否能进一步提高保护效果。互补后的DeltaPMM寄生虫恢复了糖缀合物生物合成,同时保留了亲本敲除菌株的无毒力。用hPMM2回补寄生虫免疫接种后显示出与DeltaPMM疫苗接种小鼠中观察到的类似的Th1/Th2细胞因子谱。然而,利什曼原虫感染后早期募集到引流淋巴结的活化CD4+CD44(hi)和CD8+CD44(hi) T细胞数量减少,导致hPMM2免疫接种后的保护作用降低。因此,感染早期T细胞反应的强度以及富含甘露糖的糖缀合物的缺失决定了抗利什曼原虫免疫的保护结果。