Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia
Mice deficient in LRG-47 display increased susceptibility to mycobacterial infection associated with the induction of lymphopenia
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DOI：
10.4049/jimmunol.172.2.1163
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发表时间：
2004-01-15
影响因子：
4.4
通讯作者：
Sher, A
中科院分区：
文献类型：
--
作者：
Feng, CG;Collazo-Custodio, CM;Sher, A
虽然干扰素-γ对于宿主控制分枝杆菌感染是必不可少的，但细胞因子限制病原体生长的机制还只有部分了解。LRG-47是一种干扰素诱导的GTP结合蛋白，以前被证明是依赖干扰素的宿主抵抗急性单核细胞增多性李斯特菌和弓形虫感染所必需的。为了探讨LRG-47在控制分枝杆菌感染中的作用，用禽型分枝杆菌感染LRG-47(-/-)和野生型小鼠，并分析宿主反应。LRG-47蛋白在感染野生型动物的肝脏中以干扰素-γ依赖的方式强烈诱导。LRG-47(-/-)小鼠无法控制细菌复制，但在感染后11-16周死于急性期。来自LRG-47(-/-)和野生型动物的经干扰素-伽马刺激的骨髓来源的巨噬细胞在体外对禽类支原体感染产生相同水平的肿瘤坏死因子和一氧化氮，并产生相似的细胞内细菌负荷。此外，从受感染的LRG-47(-/-)小鼠分离的T细胞中也观察到了产生干扰素-γ的预激作用。然而，重要的是，LRG-47(-/-)小鼠的分枝杆菌肉芽肿表现出明显的淋巴细胞缺陷。对这些动物的进一步检查发现，感染引发了严重的全身性淋巴细胞减少和贫血。由于LRG47(-/-)T淋巴细胞在受体重组酶激活基因-2(-/-)小鼠中既能存活又能抵抗禽类分支杆菌，LRG-47(-/-)小鼠的细胞反应和细菌控制能力的缺陷也可能与非淋巴细胞室表达的一种因子(S)有关。这些发现确立了LRG-47在分枝杆菌宿主控制中的作用，并表明在对持续感染的干扰素-伽马反应的背景下，LRG-47可以对淋巴细胞存活起下游调节作用。免疫学杂志，2004,172：1163-1168。
Although IFN-gamma is essential for host control of mycobacterial infection, the mechanisms by which the cytokine restricts pathogen growth are only partially understood. LRG-47 is an IFN-inducible GTP-binding protein previously shown to be required for IFN-gamma-dependent host resistance to acute Listeria monocytogenes and Toxoplasma gondii infections. To examine the role of LRG-47 in control of mycobacterial infection, LRG-47(-/-) and wild-type mice were infected with Mycobacterium avium, and host responses were analyzed. LRG-47 protein was strongly induced in livers of infected wild-type animals in an IFN-gamma-dependent manner. LRG-47(-/-) mice were unable to control bacterial replication, but survived the acute phase, succumbing 11-16 wk postinfection. IFN-gamma-primed, bone marrow-derived macrophages from LRG-47(-/-) and wild-type animals produced equivalent levels of TNF and NO upon M. avium infection in vitro and developed similar intracellular bacterial loads. In addition, priming for IFN-gamma production was observed in T cells isolated from infected LRG-47(-/-) mice. Importantly, however, mycobacterial granulomas in LRG-47(-/-) mice showed a marked lymphocyte deficiency. Further examination of these animals revealed a profound systemic lymphopenia and anemia triggered by infection. As LRG47(-/-) T lymphocytes were found to both survive and confer resistance to M. avium in recipient recombinase-activating gene-2(-/-) mice, the defect in cellular response and bacterial control in LRG-47(-/-) mice may also depend on a factor(s) expressed in a nonlymphocyte compartment. These findings establish a role for LRG-47 in host control of mycobacteria and demonstrate that in the context of the IFN-gamma response to persistent infection, LRG-47 can have downstream regulatory effects on lymphocyte survival. The Journal of Immunology, 2004, 172: 1163-1168.