Infection with Arginase-Deficient Leishmania major Reveals a Parasite Number-Dependent and Cytokine-Independent Regulation of Host Cellular Arginase Activity and Disease Pathogenesis
Infection with Arginase-Deficient Leishmania major Reveals a Parasite Number-Dependent and Cytokine-Independent Regulation of Host Cellular Arginase Activity and Disease Pathogenesis
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DOI：
10.4049/jimmunol.0803979
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发表时间：
2009-12-15
影响因子：
4.4
通讯作者：
Uzonna, Jude E.
中科院分区：
文献类型：
--
作者：
Muleme, Helen M.;Reguera, Rosa M.;Uzonna, Jude E.
巨噬细胞L-精氨酸代谢产物之间的平衡调节利什曼原虫感染的结果。L-精氨酸可被宿主诱导型NO合酶氧化产生NO，这有助于杀死寄生虫。相反，宿主精氨酸酶水解L-精氨酸阻断NO生成，并提供多胺，这可以支持寄生虫增殖。此外，利什曼原虫编码其自身的丝氨酸蛋白酶，其具有相当大的调节感染性和疾病发病机制的潜力。在这项研究中，我们比较了野生型（WT）L的体外和体内感染性和对宿主细胞免疫应答的影响。主要与寄生虫精氨酸酶无效突变体（arg（-））L.少校我们发现arg（-）L. major的巨噬细胞感染性在体外受损，与宿主诱导型NO合酶活性无关。与体外结果一样，arg（-）L.动物感染中的主要寄生虫在体内也显著受损，导致病变发展的延迟发作、减弱的病理学和低寄生虫负荷。尽管这种病理学减弱，但WT和arg（-）L感染小鼠的引流淋巴结细胞产生的细胞因子。在所有测试时间，Major均相似。有趣的是，在体外和体内的arg（-）比WT感染的情况下，arg（-）的酶水平显着降低，并与感染细胞内的寄生虫数量直接相关。这些结果表明，利什曼原虫编码的脱氢酶通过增强宿主细胞脱氢酶活性来增强疾病的发病机制，并且与先前的体外研究相反，宿主细胞因子应答不影响宿主脱氢酶活性。免疫学杂志，2009，183：8068-8076.
The balance between the products of L-arginine metabolism in macrophages regulates the outcome of Leishmania major infection. L-arginine can be oxidized by host inducible NO synthase to produce NO, which contributes to parasite killing. In contrast, L-arginine hydrolysis by host arginase blocks NO generation and provides polyamines, which can support parasite proliferation. Additionally, Leishmania encode their own arginase which has considerable potential to modulate infectivity and disease pathogenesis. In this study, we compared the infectivity and impact on host cellular immune response in vitro and in vivo of wild-type (WT) L. major with that of a parasite arginase null mutant (arg(-)) L. major. We found that arg(-) L. major are impaired in their macrophage infectivity in vitro independent of host inducible NO synthase activities. As with in vitro results, the proliferation of arg(-) L. major in animal infections was also significantly impaired in vivo, resulting in delayed onset of lesion development, attenuated pathology, and low parasite burden. Despite this attenuated pathology, the production of cytokines by cells from the draining lymph node of mice infected with WT and arg(-) L. major was similar at all times tested. Interestingly, in vitro and in vivo arginase levels were significantly lower in arg(-) than in WT-infected cases and were directly correlated with parasite numbers inside infected cells. These results suggest that Leishmania-encoded arginase enhances disease pathogenesis by augmenting host cellular arginase activities and that contrary to previous in vitro studies, the host cytokine response does not influence host arginase activity. The Journal of Immunology, 2009, 183: 8068-8076.