Araúzo-Bravo Marcos J, Delic Denis, Gerovska Daniela, Wunderlich Frank
Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain.
IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain.
Vaccines (Basel). 2020 Nov 13;8(4):677. doi: 10.3390/vaccines8040677.
The role of natural killer (NK) cells in the liver as first-line () effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 10-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., in expanding liver-resident NK (lrNK) cells, in immigrating conventional NK (cNK) cells; and encoding transcription factors; and encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs expression, accelerates decline of and expression, whereas it accelerates increased expression of , taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 is highly significantly ( < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of .
自然杀伤（NK）细胞在肝脏中作为抵御血液期疟疾的一线效应细胞的作用及其对保护性疫苗接种的反应尚不清楚。在此，我们研究疫苗接种对雌性Balb/c小鼠血液期疟疾诱导肝脏中NK细胞相关基因的影响。在感染10个被寄生红细胞之前，于第3周和第1周对小鼠进行疫苗接种。在感染后第0、1、4、8和11天，使用微阵列、qRT-PCR和染色体景观分析，在接种疫苗后受到保护和未受保护的小鼠肝脏中研究NK细胞优先表达的基因。血液期疟疾在感染的不同阶段诱导肝脏中特定基因的表达，即在不断扩增的驻肝NK（lrNK）细胞中、在迁入的常规NK（cNK）细胞中；以及编码转录因子；以及编码细胞溶解效应器；自然杀伤基因复合体（NKC）定位的基因，编码NK细胞受体KLRG1、KLRK1、KLRAs1、2、5、7、KLRD1、KLRC1、KLRC3，以及三种受体KLRB1A、KLRB1C、KLRB1F及其潜在配体CLEC2D和CLEC2I。疫苗接种增强了这种疟疾诱导的基因表达，但损害了 表达，加速了 和 表达的下降，而它加速了 表达的增加，其时间进程与编码成红细胞质膜蛋白的基因非常相似，已知接种疫苗可加速其在肝脏中的疟疾诱导的髓外生成。总体而言，疫苗接种重塑了肝脏NK细胞区室对血液期疟疾的反应。特别是，在第4天达到峰值的疟疾诱导的lrNK细胞扩增因外周cNK细胞的增强迁入而高度显著（<0.0001）减少，并且NK细胞与红系细胞之间的KLRB1F:CLEC2I相互作用促进了肝脏中的髓外成红细胞生成，从而对疫苗接种诱导的 致死性血液期疟疾的存活起着关键作用。
