Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence
Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence
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DOI：
10.1096/fj.201500189r
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发表时间：
2016-06-01
期刊：
影响因子：
4.8
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
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作者：
Holowka, Thomas;Castilho, Tiago M.;Bucala, Richard
利什曼原虫主要编码细胞因子巨噬细胞迁移抑制因子（MIF）的2个同源物，其在寄生虫生长或宿主-寄生虫相互作用中的功能尚不清楚。为了确定利什曼原虫编码的MIF的重要性，去除两个LmMIF基因，产生L. major的MIF（-/-）菌株。该突变株在体外正常复制，但对巨噬细胞清除的敏感性增加了2倍。与野生型菌株相比，感染mif(-/-) L. major的小鼠的寄生虫负担也减少了3倍。微阵列和功能分析显示，mif(-/-) L. major激活抗原呈递细胞的能力降低，导致t细胞启动减少2倍。此外，与野生型L. major感染小鼠相比，mif(-/-) L. major感染小鼠的炎症和效应CD4 t细胞形成减少。值得注意的是，在感染mif(-/-) L. major期间产生的效应CD4 T细胞在功能衰竭标志物方面表现出统计学上的显著差异，包括IFN-和IL-7R的表达增加，程序性死亡-1的表达减少，以及凋亡减少。这些数据支持LmMIF通过操纵宿主反应增加保护性CD4 T细胞的耗竭和消耗来促进寄生虫持久性的作用。Holowka， T., Castilho， T. M., Baeza Garcia， A., Sun， T., McMahon-Pratt， D., Bucala， R.：利什曼原虫编码的巨噬细胞迁移抑制因子同源物调控宿主免疫促进寄生虫持续存在。
Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host-parasite interaction are unknown. To determine the importance of Leishmania-encoded MIF, both LmMIF genes were removed to produce an mif(-/-) strain of L. major. This mutant strain replicated normally in vitro but had a 2-fold increased susceptibility to clearance by macrophages. Mice infected with mif(-/-) L. major, when compared to the wild-type strain, also showed a 3-fold reduction in parasite burden. Microarray and functional analyses revealed a reduced ability of mif(-/-) L. major to activate antigen-presenting cells, resulting in a 2-fold reduction in T-cell priming. In addition, there was a reduction in inflammation and effector CD4 T-cell formation in mif(-/-) L. major-infected mice when compared to mice infected with wild-type L. major. Notably, effector CD4 T cells that developed during infection with mif(-/-) L. major demonstrated statistically significant differences in markers of functional exhaustion, including increased expression of IFN- and IL-7R, reduced expression of programmed death-1, and decreased apoptosis. These data support a role for LmMIF in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cells.Holowka, T., Castilho, T. M., Baeza Garcia, A., Sun, T., McMahon-Pratt, D., Bucala, R. Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence.