Mice deficient in LRG-47 display enhanced snsceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth
Mice deficient in LRG-47 display enhanced snsceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth
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DOI：
10.4049/jimmunol.175.12.8165
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发表时间：
2005-12-15
影响因子：
4.4
通讯作者：
Sher, A
中科院分区：
文献类型：
--
作者：
Santiago, HC;Feng, CG;Sher, A
已知干扰素-γ是小鼠细胞内克氏锥虫感染的宿主控制所必需的，尽管其保护功能的基础尚不清楚。LRG-47是一种干扰素诱导的p47GTP酶，已被证明调节宿主对细胞内病原体的抵抗力。为了探讨LRG-47在干扰素依赖的控制旋毛虫感染中的可能作用，用该寄生虫Y株感染LRG-47基因敲除(KO)小鼠和野生型(WT)小鼠，并分析宿主反应。当在寄生虫接种后第12天进行检测时，LRG-47KO小鼠与干扰素伽马/KO小鼠相比，几乎与WT动物一样有效地控制了早期寄生虫血症。然而，感染LRG-47 KO小鼠的寄生虫生长在第15天出现反弹，并在第19天全部死亡。进一步的分析表明，LRG-47缺陷小鼠在整个感染过程中表现出未受损害的促炎反应。相反，在KO动物中，再激活的疾病与严重的脾和胸腺萎缩、贫血和血小板减少有关，这在WT动物中没有观察到。此外，体外研究表明，在干扰素-γ刺激的LRG-47 KO巨噬细胞中，尽管有正常表达的肿瘤坏死因子和一氧化氮合成酶2型，但细胞内对无鞭毛虫的杀伤存在缺陷，而且一氧化氮合成酶2型和LRG-47都是最佳的WN-伽玛依赖限制寄生虫生长所必需的。总之，这些数据表明，LRG-47可以通过同时调节巨噬细胞杀微生物活性和造血功能来影响病原体控制。
IFN-gamma is known to be required for host control of intracellular Trypanosoma cruzi infection in mice, although the basis of its protective function is poorly understood. LRG-47 is an IFN-inducible p47GTPase that has been shown to regulate host resistance to intracellular pathogens. To investigate the possible role of LRG-47 in IFN-gamma-dependent control of T. cruzi infection, LRG-47 knockout (KO) and wild-type (WT) mice were infected with the Y strain of this parasite, and host responses were analyzed. When assayed on day 12 after parasite inoculation, LRG-47 KO mice, in contrast to IFN gamma/KO mice, controlled early parasitemia almost as effectively as WT animals. However, the infected LRG-47 KO mice displayed a rebound in parasite growth on day 15, and all succumbed to the infection by day 19. Additional analysis indicated that LRG-47-deficient mice exhibit unimpaired proinflammatory responses throughout the infection. Instead, reactivated disease in the KO animals was associated with severe splenic and thymic atrophy, anemia, and thrombocytopenia not observed in their WT counterparts. In addition, in vitro studies revealed that IFN-gamma-stimulated LRG-47 KO macrophages display defective intracellular killing of amastigotes despite normal expression of TNF and NO synthetase type 2 and that both NO synthetase type 2 and LRG-47 are required for optimum WN-gamma-dependent restriction of parasite growth. Together, these data establish that LRG-47 can influence pathogen control by simultaneously regulating macrophage-microbicidal activity and hemopoietic function.