Oral vaccination with Salmonella enterica as a cruzipain-DNA delivery system confers protective immunity against trypanosoma cruzi
Oral vaccination with Salmonella enterica as a cruzipain-DNA delivery system confers protective immunity against trypanosoma cruzi
复制标题
DOI：
10.1128/iai.01163-07
复制
发表时间：
2008-01-01
影响因子：
3.1
通讯作者：
Guzman, Carlos A.
中科院分区：
文献类型：
--
作者：
Cazorla, Silvia I.;Becker, Pablo D.;Guzman, Carlos A.
为了刺激对克氏锥虫的局部和全身免疫反应，利用肠沙门氏菌血清型鼠伤寒沙门氏菌aroA作为克氏锥虫蛋白酶（SCz）的DNA递送系统。在小鼠模型中，我们比较了SCz单独（GI）或与携带编码粒细胞-巨噬细胞集落刺激因子（GII）的质粒的沙门氏菌共同给药，以及在SCz启动后与CpG-ODN （GIII）或MALP-2混合的重组cruzipain （rCz）增强的方案。结果表明，四次口服SCz （GI）的方案主要引起粘膜反应，其特征是免疫球蛋白a （IgA）的分泌和肠道相关淋巴组织细胞的增殖，具有弱的全身反应。相比之下，包括rCz + CpG （GIII）增强的方案在cz特异性血清IgG滴度、脾细胞增殖、γ干扰素（ifn - γ）分泌和延迟型超敏反应方面引发了更强的全身反应。与对照组相比，接种疫苗小鼠的锥马鞭毛虫攻击导致寄生虫血症水平显著降低。通过消耗CD4（+）或CD8(+) T细胞来消除保护作用。组织病理学研究和血清中作为慢性恰加斯病肌肉损伤标志的酶（即肌酸激酶、天冬氨酸转氨酶和乳酸脱氢酶）水平显示，寄生虫控制也明显体现在组织损伤的减少上。在感染的非寄生期再刺激脾细胞后，在GI和GII中观察到ifn - γ和白细胞介素-2的释放增强。我们的研究结果表明，沙门氏菌介导的Cz-DNA递送本身可以促进免疫反应的激发，从而控制克氏锥虫感染，从而减少寄生虫负荷和随后对肌肉组织的损伤。
To stimulate both local and systemic immune responses against Trypanosoma cruzi, Salmonella enterica serovar Typhimurium aroA was exploited as a DNA delivery system for cruzipain (SCz). In a murine model we compared SCz alone (GI) or coadministered with Salmonella carrying a plasmid encoding granulocyte-macrophage colony-stimulating factor (GII), as well as protocols in which SCz priming was followed by boosting with recombinant cruzipain (rCz) admixed with either CpG-ODN (GIII) or MALP-2, a synthetic derivative of a macrophage-activating lipopeptide of 2 kDa from Mycoplasma fermentans (GM. The results showed that protocols that included four oral doses of SCz (GI) elicited mainly a mucosal response characterized by immunoglobulin A (IgA) secretion and proliferation of gut-associated lymphoid tissue cells, with weak systemic responses. In contrast, the protocol that included a boost with rCz plus CpG (GIII) triggered stronger systemic responses in terms of Cz-specific serum IgG titers, splenocyte proliferation, gamma interferon (IFN-gamma) secretion, and delayed-type hypersensitivity response. Trypomastigote challenge of vaccinated mice resulted in significantly lower levels of parasitemia compared to controls. Protection was abolished by depletion of either CD4(+) or CD8(+) T cells. Parasite control was also evident from the reduction of tissue damage, as revealed by histopathologic studies and serum levels of enzymes that are markers of muscle injury in chronic Chagas' disease (i.e., creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Enhanced release of IFN-gamma and interleukin-2 was observed in GI and GII upon restimulation of splenocytes in the nonparasitic phase of infection. Our results indicate that Salmonella-mediated delivery of Cz-DNA by itself promotes the elicitation of an immune response that controls T. cruzi infection, thereby reducing parasite loads and subsequent damage to muscle tissues.