IFN-γ-Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria
IFN-γ-Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria
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DOI：
10.4049/jimmunol.1300462
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发表时间：
2013-11-15
影响因子：
4.4
通讯作者：
D'Imperio Lima, Maria Regina
中科院分区：
文献类型：
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作者：
da Silva, Henrique Borges;de Salles, Erika Machado;D'Imperio Lima, Maria Regina
在没有持续接触这种寄生虫的情况下，对疟原虫的保护性免疫丧失的机制尚未完全阐明。最近有研究表明，人类和小鼠急性疟疾期间产生的ifn - γ启动了对TLR激动剂的免疫反应。在这项研究中，我们研究了ifn - γ诱导的启动是否对维持对chabaudi疟原虫AS疟疾的长期保护性免疫很重要。感染后第60天，C57BL/6小鼠仍有慢性寄生虫血症，并能有效控制同源和异源（AJ）菌株的侵染。慢性小鼠脾脏显示效应/效应记忆（T-EM） CD4（+）细胞数量增加，这与ifn - γ诱导的启动水平增加（即ifn诱导基因的高表达和TLR高反应性）有关。在寄生虫消除后，ifn - γ诱导的启动不再被检测到，对异源攻击的保护性免疫大部分丧失，死亡率约为70%。自发治愈的小鼠血清中寄生虫特异性IgG水平较高，但效应T/T- em细胞数量、寄生虫驱动的CD4(+) T细胞增殖和ifn - γ产生与未感染的对照组相似。值得注意的是，用低剂量ifn - γ启动治愈小鼠，可恢复TLR的高反应性和控制异源攻击的能力，增加T- em细胞数量，恢复CD4(+) T细胞对寄生虫的反应。在缺乏MyD88适配器的小鼠中获得的数据支持了TLR信号对慢性小鼠CD4(+) T细胞反应的贡献。这些结果表明，ifn - γ诱导的启动是维持针对恰波迪疟原虫的保护性免疫所必需的，并有助于建立人类疟疾跨株免疫的分子基础。
The mechanism by which protective immunity to Plasmodium is lost in the absence of continued exposure to this parasite has yet to be fully elucidated. It has been recently shown that IFN-gamma produced during human and murine acute malaria primes the immune response to TLR agonists. In this study, we investigated whether IFN-gamma-induced priming is important to maintain long-term protective immunity against Plasmodium chabaudi AS malaria. On day 60 postinfection, C57BL/6 mice still had chronic parasitemia and efficiently controlled homologous and heterologous (AJ strain) challenge. The spleens of chronic mice showed augmented numbers of effector/effector memory (T-EM) CD4(+) cells, which is associated with increased levels of IFN-gamma-induced priming (i.e., high expression of IFN-inducible genes and TLR hyperresponsiveness). After parasite elimination, IFN-gamma-induced priming was no longer detected and protective immunity to heterologous challenge was mostly lost with >70% mortality. Spontaneously cured mice had high serum levels of parasite-specific IgG, but effector T/T-EM cell numbers, parasite-driven CD4(+) T cell proliferation, and IFN-gamma production were similar to noninfected controls. Remarkably, the priming of cured mice with low doses of IFN-gamma rescued TLR hyperresponsiveness and the capacity to control heterologous challenge, increasing the T-EM cell population and restoring the CD4(+) T cell responses to parasites. Contribution of TLR signaling to the CD4(+) T cell responses in chronic mice was supported by data obtained in mice lacking the MyD88 adaptor. These results indicate that IFN-gamma-induced priming is required to maintain protective immunity against P. chabaudi and aid in establishing the molecular basis of strain-transcending immunity in human malaria.